development of cellgram & clinical trials. contents company introduction mesenchymal stem cells...
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PHARMICELLPRESENTATION
Development of Cellgram & Clinical Trials
CONTENTS
COMPANY INTRODUCTION
MESENCHYMAL STEM CELLS
CLINICAL TRIALS
CELLGRAM
CASE STUDY
Ⅰ
Ⅱ
Ⅲ
Ⅴ
Ⅳ
CompanyIntroduction
Company Overview
Name
Capital
Employees
Pharmicell Co.,Ltd.
20,843B (KRW)
103 ppl
Foundation
Website
Address
May 3rd, 2002
www.pharmicell.com
12F~15F, Chungho B/D, 3-2 Nonhyun-dong, Gang-nam-gu, Seoul
CEOHYUN-SOO KIM
Business Area
Business Area
SCTP
SC Cosmetics
SC Banking
CMO Business
• CMO• Provision of SC culture media • Sales of medicine and medical
devices
• hSC conditioned media
material development and sales• hSC conditioned media
cosmetics By Pharmicell Lab
• SCTP development• Sales of HeartiCellgram-AMI• Cerebropathy therapy product• Liver disease therapy product• Spinal cord injury therapy product • Lung disease, anti-cancer therapy
product
• Adult SC banking (Twelve-adult)• Cord blood banking (Twelve-baby)
Pipeline
GMP Facilities
Manufacturing Facilities Quality Control Facilities
Concept of “SCTP”
FDA (1997) KFDA (2002)
The KFDA set up ‘the concept of cell therapy’ by revising “The regulation of safety & ef-ficacy test of drug”.
KFDA Notification No. 2001-35
The FDA proposed a new ap-proach to the regulation of human cellular and tissue-based products.Docket Number 97N-0068 (Feb. 28, 1997)
The FDA proposed the man-agement of human-derived cells or tissues to be ap-proached step-by-step based on the degree of given-risk to patients.
“Cell therapy product” means a medicinal product manufac-tured through physical, chemi-cal, and/or biological manipu-lation, such as in vitro culture of autologous, allogeneic, or xenogeneic cells.
KFDA Notification No. 2010-50(Amended on June 29, 2010)
Stem Cell Manufacturing Know-How
step1 Initial Checkup(blood test) & Bone Marrow aspiration
Hospital
Mononuclear cell(MNC) separation Grade 1A/1B
step3 Mesenchymal stem cell(MSC) separation Grade 1A/1B
step 4 MSC culture (P0 – P1) Grade 1A/1B
step5 MSC culture (P2-P4 or P2-P5) Grade 1A/1B
step6 MSC harvest Grade 1A/1B
step7 Filling Grade 1A
step8 Packaging Grade 2
step2
AboutMSCs
Bone Marrow Stromal Cell (MSC) and Hematopoiesis
HSC
MSC
soluble factorscell to cell interactionsmatrix proteins
MSC
HSC
HSC
HSC
HSC
HSC
• Hematopoiesis requires an intact and fully functioning bone marrow stroma.
• Cellular components of bone marrow stroma : macrophages, endothelial cells, fibroblasts, adipocytes and
osteogenic precursor cells
Bone Marrow Stromal Cell (MSC) and Hematopoiesis
(MSC)
Support hematopoiesis
Cultured MSC
(HSC)
(MSC)
(HSC)
(HSC)
(HSC)
Cultured MSC
HematopoiesisAll blood components: 1010/day
Marrow stromal cell / MSC106 in bone marrow
Angiogenesis
VEGF-AANGPT-1TGF- β1IL-6PDGF-AANG
Anti-apoptosis
SFRP-2SFRP-1Tβ4HGFIGF-1LIF Anti-inflammation
IL-6IL-11
Anti-Scarring(Fibrolysis)
Tβ4FGF-2MMP-1MMP-2MMP-9TIMP-1TIMP-2CTGF
STEM CELL
Stem Cells homing
SDF-1VEGF-AFGF-2CCL2SCF
Potency
• Adherent to tissue culture flask
• Positive for CD105, CD73, CD90 and negative for CD45, CD34, CD14, CD11b, CD 79a or CD19
• Ability to differentiate into osteoblasts, adipocytes and chondroblasts
• Capacity of differentiation
• Ability to secrete soluble factors that are crucial for cell survival and prolifera-tion
• Ability to modulate immune response
Minimal Criteria of MSC / Key Properties
• Ability to migrate to the exact site of injury
MSC and Skin Regeneration
MSC and Aging Process
Source: Trounson et al., BMC Medicine, 2011
(As of Jan 2012, a search of www.clinicaltrials.gov)
170 clinical trials
O(11, 6.5%)
Ⅰ(32,
18.8%)
Ⅰ/Ⅱ( 75, 44.1%)
Ⅱ(43,
25.3%)
Ⅱ/Ⅲ(3, 1.8%)
Ⅲ(6, 3.5%)
Bone marrow (120, 70.6%)
Cord blood(28, 16.5%)
Adipose tissue(14, 8.2%)
Differentiated(3, 1.8%)
Etc.(5, 2.9%)
<Clinical phase>
<Source>
MSC Clinical Trials (worldwide)
• The global market for stem cell products was $3.8 billion in 2011. This market is expected to reach nearly $4.3 billion in 2012 and $6.6 billion by 2016, increasing at a compound annual growth rate (CAGR) of 11.7% from 2011 to 2016.
• The American market for stem cell products was $1.3 billion in 2011. This sector is expected to rise at a CAGR of 11.5% and reach nearly $2.3 billion by 2016.
• The European market for stem cell products was $872 million in 2011 and is ex-pected to reach nearly $1.5 billion by 2016, a CAGR of 10.9%.
※ Ref. : 「 Global Markets for Stem Cells 」 by BCC Research (2012. 07)
Global Stem Cell Market
ClinicalTrials
Clinical Study - Stroke
Pharmicell research
Current treatments
Market status• 2nd leading cause of Korean deaths, 1st in mortality rate among diseases• Total 26,517 dead in 2010
• fundamental treatment impossible• thrombolytic agents used to open blood vessels treatment effects low and pertains to only 1~2% stroke patients
• MRI showed clear decrease in brain damage and contraction• Clear increase of ability for daily life conduct / decrease in disability• Independent walking possible after 6 months of transplant (increase in physical ability)
• Phase III clinical trial currently under progress• Clinical results secured
Indication • Occurs when blood vessel to the brain is blocked and there is damage to brain cells leading to loss of brain functions• Accompanied by speech impairment, cognitive impairment, and dyspraxia
Commercialization
Background & Objective : Mesenchymal stem cell transplantation has been shown to im-prove functional recovery after ischaemic stroke in animal studies. We examined the feasibil-ity, efficacy and safety of cell replacement therapy using culture-expanded autologous mes-enchymal stem cells (MSCs) in patients with ischaemic stroke. Methods : After standard therapy of acute cerebral infarction, we prospectively randomised 30 patients with ischaemic stroke who had had cerebral infarcts within the middle cerebral arterial territory and shown severe neurological deficits; the MSC group, i.e. autologous 1x10(8) MSCs (the dose that was effective in animal studies) intravenous infusion (n=5), and control group (n=25). Changes in neurological deficits and functional improvement were compared between the groups, for up to one year after symptom onset. Neuroimaging was per! formed serially in 5 patients of both groups. Result : All outcomes measurements were significantly improved in patients of the MSC group compared with those of the control group; the Barthel index (P=0.01 at 3months, P=0.05 at 6months, and P=0.04 at 12months) and modified Rankin score group (P=0.04 at 3months, P=0.03 at 6months, and P=0.02 at 12months) of the MSC group were consistent in identifying a trend toward improved scores during follow-up period. Serial eval-uations showed no adverse cell-related serologic or imaging-defined effects. Magnetic reso-nance imaging showed no evidence of mass formation, and atrophic changes around in-fracted area was less prominent at the follow-up imaging. Conclusions : In patients with se-vere cerebral infarcts, intravenous infusion of autologous MSCs appears to be feasible and safe and may beneficially affect functional recovery.
Department of Neurology, School of Medicine, Ajou University
Oh Young Bang,Jin Soo Lee
Clinical Study - Stroke
.6224 : 114 : 11M:F
Severity
.04663.00 ± 7.4859.32 ± 11.52Age
.68661.20 ± 41.9553.44 ± 38.22RT (days)
62.00 ± 12.04
55.00 ± 16.96
9.00 ± 20.12
127.37 ± 70.27
9.20 ± 1.79
10.60 ± 2.61
5
MSC
Clinical course
.73113.40 ± 22.21 Barthel index after 7d
.01226.40 ± 22.29 Barthel index after 3m
.05036.74 ± 23.96Barthel index after 6m
.18089.12 ± 77.36DWI lesion(ml)
.13812.16 ± 3.98NIH stroke point after 7d
.10411.60 ± 4.94NIH stroke point at adm.
25No. of patients
Pcontrol
Clinical Study - Stroke
Bart
hel in
dex (
%)
months0
25
50
75
At admission 1 3 6
<50 50-70>90
400 cases (2001-2002), Ajou University Hospital, Dept. of Neurology
Control
MSC
Inde
pen-
dent
Bed
rid
-de
n
Clinical Study - Stroke
0
1
2
3
4
5
6
7th day 3month 6month 12month
Time from onset of symptom
mo
dif
ied
Ran
kin
sco
reControl group
MSC group
7 days 3 months 6 months 12months
7 days after stroke, both groups have severe neurologic deficits. But after 6 m of MSC infusion, treated patients are able to walk alone
Clinical Study - Stroke
A. Initial DWI FLAIR at 1year B. Initial CT CT at 36 weeks
MSC group
Control groupControl group
MSC group
0
50
100
150
200
Lesion on follow-up image /Lesion on initial DWI
Ipsilateral lateral ventricule /Contralateral lateral ventricular
Perc
enta
ge
MSC group
Control group
C. P=0.019
size of ischemia* size of atrophy †
A. MRI at admission and after 1year B. CT scan at admission and after 8 months C. Size of ischemic lesion(left) and size of atrophy(right) between at admission and after follow up
Clinical Study - Stroke
Clinical Study - Stroke
Clinical Study - Stroke
※ Ref. Stem Cells 2010;28:1099-1106
Clinical Study - Stroke
Clinical Study – Multiple System Atrophy
Clinical Study – Multiple System Atrophy
Clinical Study – Multiple System Atrophy
Clinical Study – Spinal Cord Injury
• Due to unexpected accidents• Approximately 170,000 spinal damage patients in Korea
• Observing for neurological restoration and functional restoration (sensory functions, motor skills)
• Phase II and III human clinical trials under progress
• The spine which connects the brain with the body becomes damaged by trauma and causes trouble in nervous system• Partial or total loss of motor and sensory functions
Pharmicell research
Current treatments
Market status
Indication
Commercialization
• Due to unexpected accidents• Approximately 170,000 spinal damage patients in Korea
※ Ref. : Neurosurgery. 2012 May;70(5):1238-47
Clinical Study – Spinal Cord Injury
Long-term follow-up
• Subjects : 10• Inclusion Criteria : ASIA A or B• F/U : max. 55 months• Administration (total 9.8 X107 cells) 8X106 cells –spinal cord (intramedullary) 4X107 cells – intradural space 5X107 cells – lumbar tapping • Assessments : motor power grade MRI electorphysiological recording
Patient 1
• Three of 10 patients with SCIs who re-ceived direct injections of autologous MSCs showed continuous and gradual motor improvements in the upper ex-tremities and significant MRI and elec-trophysiological changes during long-term F/U.
• Direct intramedullary injection of MSCs into SCI patients did not results in per-manent complications.
Conclu-sion
Out-line
※ Ref. : Neurosurgery. 2012 May;70(5):1238-47
Clinical Study – Spinal Cord Injury
Efficacy of stem cell therapeutics proved by Dr Sangyong Chun, from Seoul Asan Hospital, from a quadriplegic
Dr Chun is checking the muscle of the patient, Park, who got better after an autologous stem cell treatment
Clinical Study – Spinal Cord Injury
Clinical Study – Alcoholic Liver Cirrhosis
• Ranked as 8th cause of death among Koreans• No. 1 cause of death for men in their 40-50s• Total 6,888 deaths in 2010
• Hardness of liver clearly decreased• Index showing improvement of liver function clearly increased• Confirmed liver tissue regeneration to improve liver function and decrease complications
• IIT complete• Preparing IND approval data necessary for commercialization • Expect to supply products at ¼ the cost of liver transplants
• Liver hardens due to excessive drinking and chronic hepatitis leading High mortality because of complications to liver failure
Pharmicell research
Current treatments
Market status
Indication
Commercialization
• Damaged liver cannot be repaired• Liver transplant is the only viable option but lack of donated livers for transplant / immunorejection / high costs
Pre-stem cell injection (X100)
Pre- Post-
(D) Laennec Scoring Sys-tem
(C) Collagen Content
(A) H&E and Masson’ Trichrome Stain
(B) Picrosirius Red Stain
Post-stem cell injection (X100)
Pre-stem cell injection (X100)
Post-stem cell injection (X100)
Liver biopsy and histomorphological analysis at pre treat-ment and post treatment. Mild. The biopsies evaluated the de-gree of fibrosis(A,B and C) and Cirrhotic change according to the Laennec System(D).
Gene expression analysis by Real time PCR. Liver Fi-brosis Relative gene expression of TGF-b1(A), Collagen(B) and a-SAM(C) in biopsies pre and post mesenchymal stem cell treatment.
(A) TGF-b1
(B) Collagen
(C) a-SMA
Pre- Post-
Pre- Post-
Pre- Post-Pre- Post-
Efficacy of Bone Marrow derived Autologous Mesenchymal Stem Cell Injection Via Hepatic Artery in Patients with Liver Cirrhosis caused by Alcohol
Clinical Study – Alcoholic Liver Cirrhosis
• In 2009, the global market for drugs used to treat liver disease was worth approximately $12.4 billion. Sales in 2010 decreased and the market did not see much progress, causing overall global sales to remain stagnant at $12.4 billion. Estimated sales in 2011 a projected $12 billion (excluding protease inhibitors). The market is expected to rise at a CAGR of 3.3% and reach nearly $14.2 billion by 2016.
• The U.S. region constituted approximately 36% of the total market for drugs used to treat liver disease in 2010 and was valued at $4.5 billion. In 2011, the market continued to decrease and will hit nearly $4.2 billion. BCC expects this market to increase in the future rising at a CAGR of 3% to reach nearly $4.9 billion by 2016.
• The European market constituted approximately 31% of the total market and was $3.8 billion in 2010. This market is expected to see a decrease in 2011 totaling nearly $3.6 billion. This market is forecast to grow at a CAGR of 1% and should be worth $3.7 billion by 2016.
Global Market Size for Liver Disease
AboutCellgram
The World’s First Stem Cell Therapy Product
Actual Procedure
Stem cells in the body
Extract stem cells
Cultivate (stem cell itself, Cell-gram)
Inject into body
regeneration in body at injured organs
Improved Damaged Part The Infusion Route(percutaneous coronary intervention)
Basic Understanding of SCTP
Source: Pharmicell Co., Ltd
Single Dose Study Repeated Dose Study Tumorigenicity
Test Group
• Negative Con. (n=40)• Test Article (n=120)※ Low, intermediate & high
dose
• Negative control (n=44), • Test article (n=92, BM-MSC: Low, intermediate and high dose)
• Blank (n=20)• Negative control (n=20, MRC- 5: embryonic lung fibroblast)• Test article (n=40, BM-MSC: low & high dose)• Positive control (n=20, HT-1080: fibrosarcoma)
Duration 4 weeks (1 time) 4 weeks (3 weeks/3 times) 6 months (1 time)
Result
• No mortality & clinical signs
• No treatment-related
changes in
body weight, food consump-
tion,
ophthalmoscopic exam.,
urinalysis, hematology, blood
chemistry and organ weight
• No significant macroscopic
and
histopathological findings
• No Observed Adverse Effect
Level (NOAEL): ≥ 2.1 x 10^5
cells/head (ap-
proximately 7 times of the
prospected clinical dose)
• There were no test substance-
related effects on clinical signs,
body weights, food consumption,
ophthalmic examination, urinaly-
sis,
hematology, blood chemistry, or-
gan
weights, necropsy and mitogen-
induced lymphocyte proliferation
• No Observed Adverse Effect Level
(NOAEL): ≥ 6×105 cells/head
(approximately
20 times of the prospected clinical
dose)
• There were no treatment-related
clinical signs, body weight
changes,
and tumorigenicity in males and
females treated with the test
substance at doses of 10×105
cells/head.
• Therefore, the test substance was
considered to be no
tumorigenicity
at doses of 10×105 cells/head
(about 40 times of the prospected
clinical dose).
Toxicology Study (injection route: iv)
LV ejection fraction
P=0.037
※ Source : 2011 ACC Academic Society Reports
LVEF
SPECT)
Initial
6 M
49.0 ±
11.7
55.0 ±
11.8
52.3 ±
9.3
53.9 ±
10.2
0.247
0.704
LVEF (E-
cho)
Initial
6 M
48.1 ±
8.0
50.0 ±
8.4
51.0 ±
9.2
50.4 ±
9.4
0.215
0.862
LVEF
(CMR)
Initial
6 M
N=10
46.1 ±
15.2
51.3 ±
13.6
N=7
54.9 ±
9.6
54.6 ±
10.3
0.197
0.591
Change of LVEF %
SPECT
Echo
Cardiac
MR
5.9 ± 8.5
1.9 ± 2.7
5.2 ± 7.6
1.6 ± 7.0
-0.5 ± 1.8
-0.3 ± 0.9
0.037
<0.001
0.049
MSC Treat-ment
(N=30)
Control (N=28) P value
Clinical Study - AMI
※ Source: 2011 ACC Academic Society Reports
Subgroup analysis : Symptom to balloon ≤ 6h
LVEF
SPECT)
Initial
6 M
46.7 ± 10.5
55.0 ± 11.5
51.0 ± 8.752.3 ± 8.9
0.1650.398
Change of LVEF %
SPECT 8.3 ± 8.3 1.3 ± 7.5 0.007
MSC Treat-ment
(N=20)
Control (N=21) P value
1. Repeat doses to evaluate dose respon-
siveness
2. Long term follow up for survival benefit
Further Studies
Clinical Study - AMI
P=0.007
• A LVEF of 40% was an important predictor of 3-year mortality (hazard ratio [HR] 6.02, 95% confidence interval [CI] 3.68 to 9.85, p 0.001).
※ Source: Am J Cardiol. 2010 Jun 1;105(11):1528-34. Epub 2010 Apr 14.
Clinical Ref. Overview - AMI
• The initial electrocardiogram showed ST segment elevation in the anterior
leads.
• Transthoracic Echocardiography demonstrated akinesia in the anterior wall with
a decreased left ventricular systolic function (EF=38.4%).
• Baseline coronary angiography (CAG) revealed a total occlusion in proximal left
anterior descending artery(LAD) and no critical stenosis in other coronary arter-
ies (Fig. 2).
Fig.1 The electrocardiogram showed ST-segment el-evation in leads of V1-V5.
Fig.2 Baseline coronary angiogram showed total occlu-sion
in the proximal left anterior descending artery.
※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)
Case Study (June 2012)
• Baseline M-SPECT showed moderate LV dysfunction (EF=33%) with large severe
fixed defect in the anterior wall (Fig. 4).
• One month after percutaneous coronary intervention, his stem cell therapy was
done.
• Follow up CAG showed a patent stent in p-LAD.
Fig.3 Percutaneous coronary intervention was per-formed
in left anterior descending artery using 3.0x34 mmResolute Integrity®.
Fig.4 Baseline M-SPECT showed moderate left ven-tricular dysfunction(Ejection fraction=33%) with large
severefixed defect in the anterior wall.
※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)
Case Study (June 2012)
Fig.5 A Helios balloon catheter (OSCAR Inc.) was lo-cated in proximal site of stent, and then stem cell culture medium was infused via intracoronary. Subse-quently, we performed ballooning every 30 seconds twice for temporarily induced occlusion of coronary blood flow.
Fig.6 Three months later, follow-up M-SPECT showed markedly reduced size of infarcted myocardium and
improved left ventricular systolic function (Ejection fraction=44%).
• Subsequently, we performed ballooning twice every 30 seconds to temporarily
induce occlusion
of coronary blood flow (Fig. 5).
• At this important point, stem cells should not be exposed with contrast because
of its toxicity.
• Three months later, follow up M-SPECT showed markedly reduced size of in-
farcted myocardium
and improvement in a left ventricular systolic function (EF=44%, almost 11%↑)
(Fig. 6).
※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)
Case Study (June 2012)
hBM-MSCs
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간질환
퇴행성뇌질환
척수손상
당뇨병
자가면역질환
심근경색화상치료
ANTI-AGING
유방재건
탈모방지및 모발재생
시각장애암질환
By Dendritic Cell
MyocardialInfarctionLiver Disease
Cerebropathy
Spinal Cord Injury
Diabetes
Auto Immune DiseaseCancer
Visual Impairment
Breast reconstruction
Anti-aging
Burn Injury
Hair loss
Expanding Indications
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