JUL Y 2016 • IS SUE 8
Published on an occasional basis, Living Insights is a source of up-to-date information for followers of the Australasian biotechnology company Living Cell Technologies (LCT)
living insights
In this
NTCELL trial update
Cell therapies are the future BIO International Convention
Message from the CEOWelcome to this issue of Living Insights.
Living Cell Technologies is in a good position, with international exposure and recognition, as we work towards our goal of
developing and commercialising the first disease-modifying treatment for Parkinson's.
We're encouraged by the positive activity on the share market and welcome our new investors.
If you haven't already, I urge you to watch the video on our website featuring Carol, a patient on the Phase I/IIa trial of NTCELL®.
She's courageous, candid and articulate about what it's like to live with Parkinson's and how NTCELL has changed her life.
Watch the video here
Ken Taylor
CEO
The Phase IIb clinical trial of NTCELL in Parkinson's disease is underwaySince the trial is placebo-controlled LCT is blinded to which patients have received NTCELL and which have received the placebo.
While ASX regulations constrain what we can disclose about individual patients in the trial we can report that manufacture and implantation have begun. The intention is to complete implants in the first group of six patients by the end of August. Then the Data Safety Monitoring Board (DSMB) has to approve the process before implants can begin for the second group. The aim is to have all patients in group two completed by the end of 2016 and group three completed by February 2017.
Results for the first three groups should be available early in the second half of next year at which point the study will be unblinded, and the patients who received the placebo will receive an implant of NTCELL at the dose determined to be most effective.
Over the past two years LCT has achieved all milestones so we're confident the study will be completed and results known in 2017.
Safety and clinical effects of NTCELL
®
[immunoprotected (alginate-encapsulated)
porcine choroid plexus cells for
xenotransplantation] in patients
with Parkinson's disease (PD):
81 to 130 weeks follow-up.
TM
Barry J Snow, MBChB, FRACP
1
, E. Mulroy, xxx
1
, Mark Simpson, MBChB, FRACP
1
, Lorraine Macdonald, RN
1
,
Arnold Bok, MBChB, MMed, FCSSA, FRACS
1
, Ken MTaylor, PhD
2
, Jenny Han, BPharm
2
, Kathleen Durbin, PhD
2
.
1. Departments of Neurology and Neurosurgery, Auckland City Hospital, Auckland, New Zealand; 2. Living Cell Technologies New Zealand Limited, Auckland, New Zealand.
Introduction
Pre-clinical studies with NTCELL in animal models of PD indicate that continuous local production
of CSF by NTCELL can result in restoration of degenerated neural functions, supporting the use of
NTCELL as a disease-modifying cell-based therapy for neurodegenerative diseases.
We conducted a Phase I/IIa clinical study at Auckland City Hospital (New Zealand), in four patients with
Parkinson's disease (PD), in order to assess the safety and clinical effects of NTCELL implanted into the
putamen. The 26 week follow-up was presented at this meeting last year. In this poster we present the
follow-up data up to 81 weeks post-implant for all patients, and up to 130 weeks for the first patient.
International Congress of Parkinson's Disease and Movement Disorders1. Patient demographics
PATIENT NUMBER 001
002 003 004
Age at consent (years) 59 61 60
68
Gender
Female Female Male Male
Disease duration (years) 23
11
53
25
6
74
32
10
78
29
UPDRS at baseline (off) 87
UPDRS at baseline (on) 27
2. MRI
NTCELL comprises of neonatal porcine
choroid plexus cells encapsulated in
alginate microcapsules. The Auckland
Island pigs, the source of the choroid
plexus cells, are extensively studied and
screened for pathogens. NTCELL is
effectively a neurochemical factory
capable of sustained Cerebrospinal
fluid (CSF) production, and secretion of
multiple neuroactive agents.
Microarray analyses of NTCELL show
highly expressed genes (Log >8) in the
following categories :
Growth and survival factors: IGF-
HSP27, HSP40, HSP47, HSP60, HSP70-2,
HSP70-4/5/8, Mortalin-2, HSP90,
HSP90B1, HSP105/110, HSBP1, HSPA5.
Proteinase inhibitors: SERPINA1,
SERPINB6, SERPING1, SERPINI1,
Cystatin C/B/EM, TIMP 1/3, MMP9.
Pre-clinical studies with NTCELL
implanted into the striatum of rats and
non-human primates show the following:
SAFETY
Absence of Porcine Endogenous
Retrovirus (PERV) transmission in rats
II,IGFP-2, FIF, API5-like 1, TGF-ß1, TGF-ß2, and non-human primates.
3. Safety
NTCELL was well tolerated with no serious adverse events.
Testing for PERV transmission in patients and partners was
negative. Minor side effects included transient headache and
cognitive change attributed to the surgical procedure.
There were no side effects attributed to NTCELL
MMP4, BMP7, VEGF, VEGF2, VEGF B, EGF, • No major organ toxicity or shortening
PEDF, CTGF, Midkine, ERV1 homolog,
HDGF (HMG protein 1-like), HRP2, API5;
FIF, CIAPIN1, Axotrophin, Endozepine).
Chemotactic factors: AMCF-II, SDF2,
SDF2L1, CXCL14, Midkine, 7B2.
of lifespan in rats compared to
age-matched controls.
LONGEVITY
Survival of NTCELL for 18 months in rats
(the normal duration of their lifespan).
Results
Immune cells and
immunoglobulins
The structure of the
alginate microcapsules
containing choroid plexus
cells. The membrane
Alignate coating
excludes large globular
Nutrients
Poly-L-Ornithine proteins (>80,000 Da) and all
Alignate core
Choroid plexus
cell clusters
cells, but nutrients, oxygen
and carbon dioxide can
diffuse freely and secreted
proteins (
diffuse out.
Secreted
proteins
2
1
Figure 1: Saggital MRI showing the cannula tract. Implanted NTCELL micro-
capsules can be seen distributed through the putamen at the end of the tract.
The plenary session at the Congress in Berlin was most informative. The overwhelming consensus seems to be that Parkinson's disease is not one disease but a number of heterogeneous diseases, characterised by movement disorders and age-related degeneration of the putamen, an area of the striatum located in the midbrain. In our clinical studies NTCELL is implanted into the putamen.
4. UPDRS, UDYSRS, PDQ-39
There was a significant mean change from baseline to Week 81
(p
Antioxidants: Ceruloplasmin, SOD-1,
SOD-2,CCS,DJ-1.PARK7,Catalase,
Selenoprotein M/N/P/S/T/W/X/1/15kDa,
MGST1, GSTA4, GSTK1, GSTM1, GSTM5,
GSTO1, GSTP2, GSTT1, GSTZ1, MGST2,
MGST3, GPX3, GPX4, GPX1, TXN, GSR1,
HAGH.
Chaperone molecules and heat-shock
proteins: Transthyretin, APOA1, APOE,
LCN7, PACRG, PARK7/DJ-1, PRNPIP,
FE65, APPBP1, APP, HSPE1, HRSP12,
EFFICACY
Histological evidence of increased
neuronal growth in rats
(data on file, LCT)
Improvement of neurological
function and histological evidence
of corresponding increase in fibre
(TH+) density in the striatum, in an
MPTP-treated non-human primate
model of PD .
10
5
0
-5
-10
-15
-20
-25
-30
-35
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 130
Weeks post implant
Patient 001
Patient 002
Patient 003
Patient 004
Average
Our clinical trial was approved
by the Ministry of Health and the
Northern A Health and Disability
Ethics Committee in New Zealand
(12/NTA/64). The trial is
registered with ClinicalTrials.gov
(NCT01734733). An extensive
and enhanced written informed
consent procedure was
completed.
Patients aged between 40 and
70 years who had previously
been accepted for Deep Brain
Stimulation according to the
Australasian Guidelines were
eligible for this trial. We implanted
40 NTCELL microcapsules
(approx. 40,000 choroid plexus
The primary endpoints of this trial were:
Occurrence of adverse events and serious
adverse events reported over the duration
of the study.
Clinical and laboratory evidence of PERV
transmission in implant recipients and partners.
The secondary endpoints of this trial included:
Unified Parkinson's Disease Rating Scale
(UPDRS) in 'on' and 'off'
Unified Dyskinesia Rating Scale (UDysRS)
in 'on' and 'off'
Parkinson's Disease Quality of Life
Questionnaire (PDQ-39) score
Positron Emission Tomography (PET) with
[18F]-fluorodopa and [11C]-tetrabenazine
The Week 26 results were presented at this
conference in 2015. Fluorodopa PET was
10
5
0
-5
-10
-15
-20
-25
-30
Figure 2: UPDRS Total
2
Methods
Figure 3: UPDRS part III motor function change from baseline
10
5
Patient 001
0
Patient 002
-5
Patient 003
-10
Patient 004
-15
-20
Average
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 130
Weeks post implant
Figure 4: UDysRS in the 'On' state score change from baseline
Patient 001
Patient 002
Patient 003
Patient 004
Score change from baseline Motor function change from baseline UPDRS change from baseline
Variations in the disease require flexible treatment which NTCELL provides. The NTCELL alginate capsule allows penetration of incoming hormonal signals that will trigger the selective and timely release of nerve growth factors that are appropriate for each individual patient. Classifying the movement disorder disease (or diseases) is only useful if it helps with treating the disease.
cells) into the putamen on the
performed at baseline and Week 26 only.
There were no significant changes in uptake
-35
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 130
Weeks post implant
side contralateral to that of
(as previously reported). This presentation follows
the greatest clinical deficit in the patients for up to 130 weeks.
each of the four patients.
Conclusion
Average
Figure 5: PDQ-39 change from baseline
10
5
Discussion
Patient 001
0
Patient 002
-5
Patient 003
NTCELL implantation met the primary
outcome variable of safety and tolerance.
The secondary endpoint of efficacy as
measured by validated neurological rating
scales and questionnaires provides
evidence of a consistent and significant
mean improvement from baseline.
The marked improvement immediately
after the procedure could relate to a
lesion effect. Similar changes were not
shown in a previous foetal transplantation
is not related to resprouting of nigrostriatal
dopaminergic nerve terminals. Efficacy
could be the result of recovery in function
of other types of neurons involved in
neurodegeneration and compensatory
mechanisms known to occur in the
striatum of PD patients.
If this study is confirmed by the recently
initiated Phase IIb study, then NTCELL
would have considerable potential as a
disease modifying agent in PD and other
-10
Patient 004
-15
Average
-20
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 130
Weeks post implant
NTCELL implantation was safe and well tolerated.
PDQ-39 change from baseline
The plenary session also emphasised the importance of long-term patient follow-up data to reach conclusions regarding efficacy in clinical trials.
study where there was a similar cannula
trajectory and implantation of tissue
into similar locations in the putamen3.
This raises the possibility of a placebo
effect or some immediate effect of
NTCELL in our clinical study.
The sustained improvement at Week 81
neurodegenerative conditions, due to a
pleiotropic effect within the brain.
The results support moving to a Phase IIb
study entitled "A placebo-controlled,
randomised, double-blind trial to assess
the safety and efficacy of xenotrans-
plantation of NTCELL in subjects with PD".
NTCELL administered via unilateral implantation into the putamen
of four patients with PD is safe and well tolerated.
There were no serious adverse events. There was no clinical or
laboratory evidence of PERV transmission in patients or partners.
81-130 weeks after NTCELL implantation, clinical
features of PD were improved in all clinical scales.
Poster presentation
post-implant in all four patients is less
easily explained as a lesion or placebo
effect. Moreover, the improvement in the
neurological scores in the first patient
remain evident at 2.5 years post-implant.
The lack of change in dopamiergic
PET measures as reported at the 2015
The study was designed in discussion with
our regulatory authorities who requested:
Define efficacy and any placebo
contribution
Define optimal dose of
NTCELL implantation
Define initial target PD
Data shows clinically and statistically sustained improvement on
clinical features as measured in the UPDRS, UDysRS and PDQ-39.
A confirmatory study has been initiated and will
complete in 2017.
A placebo-controlled, randomised, double-blind trial to assess
the safety and efficacy of xenotransplantation of NTCELL in
subjects with PD.
meeting indicates that any improvement patient subgroup
REFERENCES: 1. Treatment of CNS disease with encapsulated inducible choroid plexus cells, USA Patent application no.15/154.709, Rest of World PCT application no. PCT/US2016/032543. 2. Luo XM, Lin H, Wang W, Geaney MS, Law L, Wynyard S, Shaikh SB,
Waldvogel H, Faull RL, Elliott RB, Skinner SJ, Lee JE, Tan PL. (2013) Recovery of neurological functions in non-human primate model of Parkinson's disease by transplantation of encapsulated neonatal porcine choroid plexus cells. J Parkinsons Dis. 3(3):275-291.
3. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB. (2003), A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol. 54(3):403-14.
At the Congress, Dr Barry Snow presented 81 week+ data on the safety and clinical effects of NTCELL in patients with Parkinson's disease.
You can view the poster here
The presentation was very well received. Impressions are that LCT is at the cutting edge of Parkinson's research and that NTCELL is a novel technology. The long-term data from the Phase I/IIa trial, demonstrating that all measurements of Parkinson's disease showed improvement, is impressive. Those at the
Congress also felt that it is unlikely that the efficacy of NTCELL can be placebo at 81 weeks post implant.
There was also general agreement that the design of the Phase IIb trial is very well thought out and will produce answers to the key questions that will enable NTCELL to proceed to a product launch.
c
Ph repla was la dopamin
since then. Mor
Cell therapies are the futureNew therapies in development for Parkinson's disease can be grouped in three areas of research: pharmaceuticals, stem cells and
ell therapies.
armaceuticals have focused on dopamine cement therapy. The gold standard, Levodopa, unched 50 years. Unfortunately, no new
ergic agent has effectively improved on this eover, all dopaminergic agents including
Levodopa treat symptoms only and are effective for a limited time.
They do not stop the progression of Parkinsons disease.
Meanwhile companies researching stem cell treatments are foundering.
Stem cells are difficult and costly to produce and are very unstable. Once they're reprogrammed they have a short shelf life, usually hours. There have been numerous stories in the media questioning whether stem cell treatments are all hype or the next big hope for the future of regenerative medicine.
In May this year Reuters reported that StemCells Inc was winding down operations after the company terminated a mid-stage trial testing its therapy in spinal cord injury. The treatment's cost efficacy ratio apparently could not justify continuing the study, given the financial resources the company had available.
Read the Reuters article here
In 2011, Geron Corp said it would pull the plug on its stem cell research and
Precision medicineNot all treatments work for everybody with Parkinson's disease due to the heterogeneity of the disease. As in many other chronic illnesses current research is focused on developing treatments to provide personalised response to these heterogeneous diseases. Success would promise greater efficacy which would help justify the cost of expensive targeted treatments.
This goal has led to the term 'precision medicine' being the target or requirement for advanced and expensive treatments that promise disease modification.
Due to its ability to respond specifically to signals in individual patients according to their neurodegenerative disease type and deterioration, NTCELL treatment certainly has the qualities required for a precision medicine. This is reflected in efficacy data in the clinical data presented at the Berlin conference.
All patients in the Phase I/IIa trial improved in all measurements of Parkinson's after NTCELL implantation. But there is obvious variation in each patient's individual rate and type of improvement. That would be expected and is encouraging as it is consistent with NTCELL's adaptive ability and plasticity.
BIO International ConventionAt the BIO International Convention in June,
LCT had a series of meetings with a broad range of
living insights 2
LCT is incorporated in Australia with its operations based in New Zealand.
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Phone: +61 2 9239 0277
Email: info@lctglobal.com
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focus on its experimental cancer treatments. Consequently, analysts are not
optimistic about the future of other stem cell research companies in the field of
attendees, including pharmaceutical and biotech
companies, universities and investors, discussing
regenerative medicine.
Neuroprotection or neurorestoration will require multiple and targeted therapies. This can only be achieved with cell therapy. The choroid plexus cells in NTCELL are not stem cells that have been reprogrammed. They are naturally occurring cells and are stable for over 60 days once purified. The choroid plexus is critical to the normal functioning of the brain as it provides neuroprotection and produces cerebrospinal fluid (CSF). Aging causes reduction in function, and the production of CSF halves. NTCELL is restorative: it does this by a pleiotropic
scale up technologies, partnering opportunities and potential investment.
This was an excellent opportunity to gauge our progress and assess the competitive landscape. The general sentiment was very positive.
LCT is making good progress and our science and clinical trial programme are world class.
We had a number of interesting meetings to discuss potential opportunities for the
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Photo by: Clifton Fuller
effect having the capacity to synthesise and release a host of neuroprotective agents which we have identified by microarray and gene chip analysis.
commercialisation of NTCELL once the current Phase IIb trial is completed next year.
Ken Taylor attending the BIO International Convention
LCT DISCLAIMER: This document contains general background information about the Company's activities current at the date of 25/7/2016. It is information given in summary form and does not purport to be complete. It is not intended to be relied upon as advice to investors or potential investors and does not take into account the investment objectives, financial situation or needs of any particular investor. This should be considered, with or without professional advice, when deciding if an investment is appropriate.
Living Cell Technologies Limited published this content on 26 July 2016 and is solely responsible for the information contained herein.
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