Development of Cellgram & Clinical Trials. CONTENTS COMPANY INTRODUCTION MESENCHYMAL STEM CELLS...

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


.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


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


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


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


※ Ref. Stem Cells 2010;28:1099-1106


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


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


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 – 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.



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).



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

THANK YOU

Development of Cellgram & Clinical Trials. CONTENTS COMPANY INTRODUCTION MESENCHYMAL STEM CELLS...

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