Transcript ppt

ASX: LCT - OTCQX: LVCLY
Bioscience Enterprise Forum
7 August 2009
1
Replacing Lost Cells
LCT products in Development and Clinical Trial
DIABECELL®
• Porcine islet cells within micro-capsules injected into abdomen
to form artificial insulin producing tissue
• In Phase I/IIa Clinical Trial
NeurotrophinCell®
• Porcine choroid plexus cells producing neurotrophins implanted
to repair endogenous brain and nerve tissue
• Pre-Clinical Development and Research
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DIABECELL®
•
Protective
Encapsulation
Aim:
Delivery of insulin in a regulated manner
Reliable source of live insulin producing cells
Simple laparoscopic procedure
Islet
Cells
No immunosuppressive drugs
•
Composition
Porcine pancreatic islets
Purified Sodium Alginate
Polyornithine
Saline
Product:
Encapsulated Neonatal Porcine Islets
•
Indication:
Insulin deficiency, Type 1 diabetes
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DIABECELL®
•
Cells excised from piglets and coated in
patented alginate-based gel to form
microspheres
•
Microspheres injected into patient using a
laparoscope incorporating endoscopic
placement
•
Engineered structure of microspheres
enables nutrients to reach cells but
prevents immunological rejection of cells
•
Immunosuppressants not required
•
Cells function naturally in body
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NanoBioCapsule Attributes
Strong, Elastic Physical Barrier
Unrestricted Cell Viability
Nutrients
Allow Inward Nutrient Diffusion
Outward Protein and Metabolite Release
Immunoisolation
Control Internal Cell Attachment
Biocompatible
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Program for a Safe and Effective Product
Regulatory Guidelines
US FDA Guidance for Industry on the Source Animal, Product, Preclinical and Clinical Issues
Concerning the Use of Xenotransplantation Products in Humans 2003
US Department of Health & Human Services Secretary’s Advisory Committee on Xenotransplantation
(SACX) Recommendations, 2004
US Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation 2001
WHO Guidance on Xenogeneic Infection/Disease Surveillance and Response: A Strategy for
International Cooperation
The European Agency for the Evaluation of Medicinal Products, Points to Consider on Xenogeneic
Cell Therapy Medicinal Products
New Zealand Government Gene Technology Advisory Committee Xenotransplantation Checklist –
Addendum to Guidelines for Application to GTAC
Draft Guidelines for Preparation of Applicants Involving Clinical Trials of Xenotransplantation in New
Zealand
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Regulatory Approvals
NEW ZEALAND
Medsafe Good Manufacturing Practice (GMP) certification for manufacture of DIABECELL® for use in humans:
Approval updated for current product in December 2006 , then annually
IANZ, International Accreditation New Zealand: accreditation for Molecular Diagnostic Laboratory to carry out
diagnostics tests relevant to xenotransplantation: Approval 2007, then annually
GTAC, Gene Technology Advisory Committee through Medsafe:
Submitted August 2006 Approval 2007
•
Ethics and cultural consideration
•
Safety: pig herd, porcine endogenous retrovirus and diagnostic assays
•
Public Health, long term monitoring
•
Pre-clinical Data/Efficacy
Regional Ethics Committee including Maori Review Research Committee
Approval 2007
Minister for Health
•
National Health Committee
•
Ministers Peer Review of Monitoring Protocol
•
Approval Jun 2009
RUSSIA
•
•
Scientific Committee Sklifosovsky Research Institute of Intensive Care Medicine 2006
Ethical Committee Sklifosovsky Research Institute of Intensive Care Medicine 2006
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Critical Capabilities for Clinical Trial
High Health Status Pigs:
•
US FDA Guidelines 2003
Molecular Diagnostic Laboratory
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International Accreditation New Zealand certified
Manufacturing Plant:
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GMP certification annual recertification and audit
•
Cell Processing
•
Encapsulation Technology
•
Toxicity data
•
Quality Certified Encapsulated Product
Preclinical/Clinical Data
•
Safety and efficacy studies in animals:
•
Data from two patients implanted with prototype
Monitoring
•
Safety monitoring for donors and recipients
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High Health Status Closed Pig Herd
High health status pigs: US FDA Guidelines 2003
•
Source Herd: Absence of xeno-relevant viruses, bacteria and parasites. Does not secrete pig
endogenous retroviruses. A closed herd bred in isolation (across 2 facilities): 3 yr health records
and regular monitoring . Three generations without mammalian content in feed. NULL pigs
•
Pig Breeding Facilities and Operations: Two herds in North & Southland, Concession to
remaining pigs on Auckland Island
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Health Monitoring of pig herd. Panel of tests by accredited laboratory. Donor database.
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Xenotransplantation Risk Assessment and Risk Management Strategy Report by Morris,
Jackson, Stevenson, Pearce: Professor Roger Morris, Massey University
Auckland Islands - NZ
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Cell Processing of Encapsulated Cell Product
Process Flow Diagram
Transport of donor
transportation times
conditions
Preparation of donors
Equipment
Materials
Reagents
medications
Surgical
anaesthetics
exsanguination
surgical procedure
warm/cold ischaemia time
TMRE
Cell processing
enzyme digestion
QC of cells
pre-encapsulation
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Manufacturing Consistency 2004-2007
A
Islet Yield
B
Islet MIR
ANOVA p<0.0001 d3 vs d4's
p=NS for d4's
***
800
uU/100 IEQ/h
IEQ/g pancreas
100000
80000
60000
40000
20000
0
ANOVA p = 0.007
d3
d4
96-102 d4
. 53-94, 2004-5
2006
BR Number and Day
103-109 d4
2007
*
*
d3
d4
600
400
200
0
96-102 d4
. 53-94, 2004-5
2006
BR Number and Day
103-109 d4
2007
Data are mean + 95%
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Shelf Life Stability (BR103-109)
Islet Viability
% Viability
105
100
95
90
85
DB 4
5-7
18
25
26
29
32
40
BR Day
Data are mean + SD
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Shelf Life Functional Stability (BR103-109)
Islet MIR
**
**
**
29
32
40
uU/100 IEQ/h
800
*
600
400
200
0
DB 4
5-7
12
15
16-7
18
21-2
25
26
BR Day
13
Islet Maturation
Insulin
Glucagon
CK7
day 1
(free islets)
day 4
(free islets)
day 35
(encapsulated islets)
BR109 Clinical Batch 4μm, 40x
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Islet Maturation
BR109 Clinical Batch
Glucagon
% Positive Staining per islet
50
40
30
20
10
0
d1f
d4f
d5e
Time Point
d15e
d35e
% Positive staining per islet
% Positive Staining per islet
Insulin
CK7
55
50
45
40
35
30
25
20
15
10
5
0
d1f
d4f
d5e
d15e
d35e
Time Point
100
75
50
25
0
d1f
d4f
d5e
d15e
d35e
Time Point
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Cell Encapsulation
Cells
Alginate
Suspension
Coating
Agents
Alginate
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Capsulation Wall Integrity
Wall thickness
14-18 um
Immune Cells
Nutrients
Insulin
Unacceptable
capsule
with
compromised
wall
Alginate Coating
PLO
Alginate
Islet of Langerhans
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3-D Structure of APA Capsule Membranes
Atomic Force Microscopy
Pores around
undulating surfaces
Scans performed at the top position of
the APA capsules. The undulating
surface is quite homogenous and
smooth with pores (Arrows)
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APA Capsules In Vivo Stability
Scanning Electron Microscopy (SEM)
APA capsules retrieved from the
peritoneum of model animals
Capsules remain intact and without pitting
defects after 215 days with ultrapure
alginate (enhanced formulation)
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Stability of APA capsules: In vivo
APA capsules remained stable for more than nine months
•
•
Enhanced Formulation: Shoulder
at 1550 cm-1 associated with the
amide bond of PLO layer detected
as a small amplitude peak, and the
carboxyl peak of the alginate
component at 1590 cm-1 maintain
uniformity.
Baseline Formulation: Transition
from day 28 to day 60, where the
amount of surface pitting reaches
the level to completely shift the
spectrum to that of PLO.
Fournier Transformed Infra Red Spectroscopy
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Capsule Strength
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Biocompatibility studies: APA capsules
In vivo studies:
Cluster of APA
capsules in
peritoneal cavity
with high
vascularization.
Capsules
remain clear.
Viability of
cells: >90%
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STZ Diabetic Rat Study
Dose Response
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STZ Diabetic Rat
Clusters of encapsulated islets showing capillary vessels on the
surface 12 weeks after transplantation.
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MH Laparoscopy 9.5 years
after Transplantation
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MH Retrieved Capsules 9 years after
Transplantation H&E
H&E x 10
H&E x 20
Islets inside capsules showing well structured endocrine cells.
Insulin
Glucagon
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DIABECELL® Prototype Functional
after 10 years
70.0
Porcine
60.0
Standards
OGTT 0
Insulin uU/mL
50.0
Human
OGTT 60
40.0
OGTT 120
30.0
20.0
10.0
0.0
14
14.5
15
15.5
16
16.5
Elution Time (min)
In Vivo Porcine Insulin
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DIABECELL® Phase I/IIa
In Moscow 2008
This patient has had type 1 diabetes
for 15 years. She has had implants
of DIABECELL® and is presently off
insulin injections
A world first independence from
injected insulin following
encapsulated porcine islet implant
without immunesuppression
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DIABECELL® Phase I/IIa Clinical Trial:
clinical effect at lowest dose
Russia preliminary data: Open label study protocol LCT/DIA-07R
Site: Sklifosovsky Institute, Moscow, Russia
CRO: Geny Research, Boston, USA
Principal Investigator: Prof N Skaletsky
Patient #
Implants
Follow Up
weeks
Insulin
Pre-enroll
Insulin
Change %
HbA1c %
Pre-enroll
HbA1c %
Current
1
2X
96
113
-33
7.1
6.1
2
3X
84
22
-100
8.2
7.1
3
2X
72
60
-12
10
7.4
4
2X
60
30
-10
7.6
6.5
5
2X
30
68
-29
9.8
7.2
6*
1X
20*
41
-
8.5
8.5
7
1X
18
37
-100
8.3
4.8
*Patient lost to follow-up after 20 weeks. Insulin Pre = Daily insulin dose before implant . Insulin % change = Current
daily dose change from pre implant baseline HbA1c =glycated hemoglobin , an indicator of blood glucose control.
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DIABECELL® Phase I/IIa Clinical Trials
Patient R001 preliminary data:
Implant Jun 2007
Retrieved Capsule Dec 2007
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Porcine Insulin In Vivo
Insulin Detection in Post HPLC Eluates
Patient# 1 before and after glucagon stimulation
Porcine Insulin
120
100
Insulin (Relative)
80
60
40
20
Human Insulin
0
12min
20sec
30
40
50
13 min
10
20
30
40
50
14 min
10
20
Elution Time
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DIABECELL® : Preliminary Phase I/Ila Data
Safety:
• No significant adverse events. No evidence of zoonotic (animal to human)
infections. Multiple implants are safe.
Benefit:
• Clinical benefit up to 96 weeks to date indicating no
immune rejection without use of immunosuppressive drugs
• Reduction in daily insulin dose . Two of seven patients off insulin
• Normalized HbA1c reflecting good blood glucose control
• No clinical hypoglycaemia
• Micro-capsules retrieved during second implant were intact and
contained live cells showing no evidence of immune injury
• Detection of porcine insulin in blood indicating a functional implant
Implications:
• Implanted cells produce insulin in patients and provide benefit
• Expect to benefit more patients with higher doses
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NZ Government Authorization
A milestone in the expansion of LCT’s clinical trial programme
•
The Minister of Health has authorized LCT’s clinical trial in NZ
•
This trial will include 8 patients to be treated with DIABECELL
4 patients - 10,000 IEQ/kg (medium dose)
4 patients - 15,000 IEQ/kg (high dose)
•
Aim of trial is to determine the optimum dose and confirm safety
•
Trial to be conducted by Dr John Baker, Clinical Director of Diabetes
Program at Middlemore Hospital
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Integrating Operations Towards
Commercialization with Strategic Alliances
CLINICAL DEVELOPMENT
Phase I/IIa Trials
18 Patients
COMMERCIAL
Pivotal Data Patients
N = 50
Approval of Non-Human
Islet Cell Implant 2012
PIG BREEDING IN NZ
20 Sows for supply to
Phase I/IIa Trials
50 Sows for supply
to Pivotal Trial
New Site for 500 Sows and
Replicate optimum units
GMP MANUFACTURING IN NZ
Pilot
GMP Facility
2008-2009
Scale-Up for supply
to Pivotal trial
2010-11
Scale-Up & Set-Up
of New Site for
Product Manufacturing
2012-13
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LCT to Scale Up to Meet Market Demand
All LCT Cell Products Use Porcine Cells
•
•
•
•
Scale-up is straight forward
Modular facilities for stepped expansion
~Fifteen (12 – 18) piglets required for each patient
Breeding program will provide sufficient cells for commercial volume
within 3 yrs
• 1,200 patients could be treated within 3 yrs of expansion from 100 sows
Females
(for breeding)
Males
(used for cells)
Number of
Patients
Treatable*
Year
Sows
Piglets
1
100
1,000
500
500
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2
600
6,000
3,000
3,000
200
3
3,600
36,000
18,000
18,000
1,200
*The number of piglets required to treat one patient depends on the weight of the patient and the dose.
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DIABECELL® Commercial Model
LCT Manufacturer
& Supplier
Clinical Service
Provider
Diabetes
Patient
Breed pigs
Establish Clinical
Center of Excellence
Consults Diabetes Physician
Manufacture DIABECELL®
Supply DIABECELL®
Diabetes Physician refers
Patients and conducts
pre-implant tests
Train Clinical Teams
Test for potential infections
and maintains implant
register
Negotiates re-imbursement
with public or private
funders
Surgeon implants to LCTapproved procedure
Provides Informed Consent
For surgery and
post Implant follow-up
Blood tests at intervals
as advised by Physician
Surgical facilities and
DIABECELL® handling and
short-term storage
Diabetes Physician
Follow-up of recipient
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NeurotrophinCell®: New Treatment Paradigm
NTCELL
Alginate encapsulated porcine choroid plexus cells
• Choroid plexus cells secrete brain reparative hormones
• NTCELL secretes BDNF, GDNF, NT-3 and many other
neurotrophins
• Neurotrophins protect brain and nerve cells from
degeneration or injury
• Neurotrophins recruit natural progenitor cells (stem cell like)
to the site of disease and injury and enhance repair
• NTCELL has been implanted in the brain of study animals
and shown to be tolerated with cells surviving beyond 6 months
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NeurotrophinCell for Neurologic Disorders
• Potential treatment for Stroke, Huntington’s disease, Parkinson’s
disease, brain injury, hearing loss from auditory nerve degeneration
• NTCELL has shown benefit in restoring function and decreasing the
size of the lesion in the
Parkinson’s Disease and Stroke models in rats
Huntington’s disease models in the rat and monkey
Untreated
Treated
Rat brain sections from stroke model
White areas indicate damaged brain tissue
19
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Porcine Bio Products
Cell Products
Choroid Plexus
Pancreatic islets
Liver cells
Biologics
Amylases, Lipases
Factor VIII, Heparin
Tissues
Heart valves
Dermal, Collagen
Small Intestine Submucosa
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Company Structure
•
•
•
•
Formed in 2003
Acquired NZ operation, IP & 17+ years of R&D
Listed on ASX September 2004
Listed on OTCQX June 2008
% Shareholding
• Shareholding :
As at 25 May 2009
Shares held No of Holders
Australia
New Zealand
USA
Elsewhere
86,733,357
66,050,325
82,100,140
3,414,930
238,298,752
1,319
404
42
41
1,806
USA
35%
Elsewhere
1%
Australia
36%
New Zealand
28%
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A new bioindustry for New Zealand
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