The Adult Stem Cell Company

Building Blocks for Better Health

Our MissionOur Mission

“Mesoblast Limited aims to become the world leader in novel therapeutic treatments for patients with bone and joint diseases.

Our primary focus is the rapid and successful commercialisation of a proprietary, high-margin, adult stem cell platform for the

treatment of conditions with very large, unmet global markets, including bone fractures, spinal disease, damaged joint cartilage,

and intervertebral disc disease”.

Stem Cells

• building blocks for blood, bone, cartilage, fat, vasculature, heart muscle

• can be extracted from various sites• can be used to repair and regenerate a wide range of tissues and

organs

Advantages Of Stem Cells Over Other Medical Therapies

• natural biologicals, safer, less likely to have side-effects

• regenerate tissues, reducing long-term health care costs

• restore function and quality of life

Stem Cells Are Human Building BlocksStem Cells Are Human Building Blocks

Advantages Of Adult Stem Cells Over Embryonic Stem Cells

• no ethical issues surrounding embryo creation and destruction• more mature, hence shorter and less costly development processes• significantly reduced risk of cancer formation• not recognized as foreign by immune system of an unrelated party

Therefore, Adult Stem Cells Are Much Closer To Market

Adult Stem Cells: The Right Building BlocksAdult Stem Cells: The Right Building Blocks

Adult Tissue Contains Two Types of Stem Cells:

• haematopoietic precursor cells:

frequent; blood, bone marrow precursors

• mesenchymal precursor cells (MPC):

rare; bone, cartilage, fat, muscle, artery precursors

Advantages Of Mesenchymal Precursors Over Haematopoietic Precursors:

• if isolated, can be easily cultured and expanded

• can generate various tissue types needed for functional restoration• not recognized as foreign by immune system of an unrelated party

Adult Stem Cells: Adult Stem Cells: Haematopoietic vs MesenchymalHaematopoietic vs Mesenchymal

BM + stem cell-binding antibody

second binding reagent

microbeads (Miltenyi)

MACSmagnet

1 hour, on ice

1/2 hour, on ice

1/4 hour, on ice

Bone Marrow (BM)

Proprietary MPC IsolationProprietary MPC Isolation

Competitive Advantages:Precise identification, ease of isolation and scale-up• 1000-fold purer initial stem cell pool• homogeneous population, high rate cell division• efficient large-scale expansion• lower costs of cell culture process• greater potency of expanded, cultured product

Bone Marrow

spin

density solution

adhere to dish

mixed cellculture

Historical Isolation MethodHistorical Isolation Method

other cell types

bone

Adult Stem CellSelf-Renewing

cartilage

Mesenchymal Precursor Cell,

MPC

Stem cellDifferentiated cell

MPCs Give Rise To Various Tissue Types:Potential Therapeutic Markets!

MPC Isolated

and Cultured

heart muscle

smooth muscle

Orthopaedic

Cardiac

arteriole

Very Large, Unmet Orthopaedic MarketsVery Large, Unmet Orthopaedic Markets

1. Bone Regeneration/Fracture Repair:(a) delayed or non-union fractures (>500,000 in US annually)

(b) vertebral fusion (300,000 in US annually)

(c) osteoporosis-related fractures (>700,000 vertebral, femoral neck in US annually)

existing therapies inadequate, use of own bone traumatic, MPC regenerate bone

2. Vertebral Disc Regeneration

affects 20% of population, results in back pain and nerve impingement

existing therapies inadequate, MPC produce material similar to disc cartilage

3. Cartilage Regeneration in Joints

(a) chronic arthritis of knee ( >800,000 arthroscopic knee surgery in US annually)

(b) acute meniscal tears

existing therapies inadequate, MPC produce material similar to articular cartilage

Very Large, Unmet Cardiovascular MarketsVery Large, Unmet Cardiovascular Markets

1. Acute Myocardial Infarction (AMI or Heart Attack) >1.1 million heart attacks in US annually 46% develop heart failure due to loss of heart muscle <6 years existing therapies inadequate MPC can increase blood vessels, protect and rebuild heart muscle

2. Congestive Heart Failure (CHF) affects 5 million Americans (2% of the population) 550,000 new US cases annually existing therapies modest efficacy, symptomatic relief only MPC can rebuild heart muscle, alleviating the condition

3. Peripheral Artery Disease (PAD) and Wound Healing >8 million in US suffer from PAD >400,000 angioplasties annually to prevent limb amputation >800,000 diabetic foot ulcers annually MPC likely to improve blood flow to limbs

Delivering A High-Margin Business Model: Delivering A High-Margin Business Model: An “Off-the-Shelf” ProductAn “Off-the-Shelf” Product

• lack of immune activation: one “universal” donor provides MPC for multiple unrelated recipients

(allogeneic), contrasting with other cell therapies (autologous)

• purity of MPC starting material:one “universal” donor can provide easy scale-up, many dosages

• easy access to source material:pay “universal” donors using existing FDA guidelines

• centralised manufacture and distribution:commercial quantities of clinical-grade MPC product easily delivered to

market as an “off the shelf” product

• pharmaceutical range profit margins

• proprietary MPC technology -- long term market protection

Strategic Vision: Biological Therapy To Complement Strategic Vision: Biological Therapy To Complement Existing Device MarketsExisting Device Markets

Orthopaedics

MPC may be combined with

• cements/polymers for fractures (e.g Zimmer, Smith & Nephew, Johnson & Johnson)• fracture repair devices (e.g. Kyphon)• vertebral cages for vertebral fusion (e.g. Medtronic)• other biologicals for bone/cartilage regeneration (e.g. Medtronic, Stryker)• delivery devices for percutaneous injection into vertebral disc/knee cartilage

Cardiovascular

MPC may be combined with

• catheters for coronary/myocardial injection (e.g Johnson & Johnson, Guidant, Medtronic)• minimally invasive surgical delivery devices (e.g. Ethicon, Guidant, Medtronic)• devices/biomaterials for wound healing (e.g. Johnson & Johnson)

Executing Results-Oriented Commercial StrategyExecuting Results-Oriented Commercial Strategy

• milestone-driven and outcome-focused

• continuous engagement of strategic corporate partners to generate early revenues in multiple fields,

geographiese.g. orthopaedic delivery companies, cardiac catheter companies, Big pharma

• minimise corporate costs, whilst maximising intelligent use of outsourcing

• deliver therapeutic products to increase quality of life and materially reduce health care costs

Clinical trial protocolClinical trial protocol

Australian human trialsAustralian human trials

• orthopaedic (auto)orthopaedic (auto)

• cardiovascular (auto)cardiovascular (auto)

Safety/toxicologySafety/toxicology

GMP processGMP process

FDA/IND filing (allo)FDA/IND filing (allo)

• orthopaedicorthopaedic

• cardiovascularcardiovascular

IND approval/US trialsIND approval/US trials

IP developmentIP development

Corporate partnershipsCorporate partnerships

Milestone-Driven, Rapid CommercialisationMilestone-Driven, Rapid Commercialisation

2005 2006 2007

Cardiovascularacute ischemia,

heart failure

FDA IND

Orthopedic long bone fracture,

vertebral discknee OA

Orthopedic

bone fracture,

spine fusion

Cardiovascular chronic ischemia,catheter delivery

Clinical Studies

Allogeneic Ib/IIarandomised,

controlled

Cardiovascular myocardial infarct,

catheter delivery

Orthopedic

Clinical Studies

Autologous Ibopen label

bone fracture, spine fusion

GMP Process forAllogeneic cells

mAb productionimmunoselection

serum-free culture,batch scale-up

Large Animal Studies (sheep)

AllogeneicTox/Efficacy

GMP process for Autologous cells

immunoselection,

culture, scale-up

GMP facility immunoselection,

batch scale-up

IND Development Plan

• contract development and supply agreement for GMP mAb for cell isolation

• contract FDA-licensed cell culture facility in US for allogeneic batch production

• contract Australian cell culture facility for autologous cell production

• optimise cell culture conditions, including serum-free media

• contract Australian medical centres for autologous clinical trials

• contract US and other medical centres for allogeneic clinical trials

• contract GMP facility for analogous mAb/cell culture conditions for sheep cells

• contract animal facilities for orthopedic/cardiac sheep studies (tox/efficacy)

Benefits of Autologous Human Clinical Trials

• optimise ex vivo culture process• improve cell engraftment and survival (e.g. matrix) • identify appropriate clinical indications amenable to therapy• determine optimal cell dose for safety/efficacy• maintain careful registry of adverse events• determine best route of administration• early validation of technology

Data valuable for inclusion in FDA dossier for IND application to initiate safety/efficacy trials with allogeneic cells

Early AchievementsEarly Achievements

External Validation

December 2004, floated with exceptional institutional and retail investment support, share price has remained significantly above issue.

Mesoblast Chief Scientific Advisor awarded $1.5 million grant from Australian National Health & Research Medical Council for mesenchymal adult stem cells.

substantial early interest from a number of leading global medical device and pharmaceutical companies re possible collaborative and commercial relationships.

Organisational

project management, regulatory, and clinical groups established, working in concert with Angioblast team to ensure efficient execution of the Joint Expenditure Program.

February 2005, Mesoblast regulatory team attended FDA advisory meeting, which served to reinforce regulatory pathway for cellular therapy in orthopedic indications.

Early Achievements, C’td.Early Achievements, C’td.

Regulatory

FDA-licensed manufacturing facilities have been identified for large-scale GMP production of MPC to be used in pivotal, multi-center clinical trials for FDA approval.

key US orthopaedic and cardiovascular opinion leaders with extensive FDA experience in pre-clinical safety and toxicologic studies have been identified. 

Pilot Clinical Trials

Pilot Clinical Trials will commence in Australia this year, evaluating safety and efficacy of autologous (patients’ own) MPC. Specific advances include:

o identification of lead orthopaedic and cardiovascular clinical indications o selection of key Australian opinion leaders and hospital sites o preparation of Ethics Committee Submissions well advanced   o contracting of Cell Therapies Pty Ltd, the cell processing facility of the Peter MacCallum Cancer Centre in Melbourne, to manufacture MPC for these trials

Mesoblast has developed a communications strategy to ensure that the market is thoroughly informed in a timely basis on the progress of the Pilot Clinical Trials.

Market Guidance For Second Quarter 2005Market Guidance For Second Quarter 2005

Regulatory

formalise contractual arrangements with FDA-licensed manufacturing facilities for large-scale GMP production of MPC to be used in pivotal, multi-centre clinical trials for FDA marketing approval.

formalise contractual arrangements with key US orthopaedic and cardiovascular opinion leaders to perform pre-clinical safety and toxicologic studies. 

Pilot Clinical Trials

complete Ethics Committee submissions to multiple Australian hospitals for Pilot Clinical Trials evaluating safety and efficacy of autologous (patients’ own) MPC in lead orthopaedic and cardiovascular clinical indications.

while timing of ethics approval, patient recruitment and enrolment will be at sole discretion of the medical centres and the clinicians involved, Mesoblast’s goal is to commence Pilot Clinical Trials in as short a timeframe as possible. .

Experienced Board of DirectorsExperienced Board of Directors

Chair Mesoblast: Michael Spooner - ex Ventracor MD & CEO

Directors: Donal O’Dwyer - ex worldwide President Cordis (J&J)

Byron McAllister - ex VP Ares-Serono (FDA expert)

Prof. Silviu Itescu - Columbia (USA) and Melb. Uni., Corp & FDA advisor

Chair Angioblast: Carter Eckert - ex CEO Knoll, ex Pres Baxter Pharmaceuticals

Chair SAB: Prof. Silviu Itescu

Members: Prof. Stephen Graves - Director Orthopaedic Research, Royal Melbourne

Prof. Robert Graham - Exec. Director Victor Chang Institute, Sydney

Prof. Henry Krum - Pfizer Global Advisory Board

Prof. Richard Gilbert - Consultant Lilly&Co., Merck, GlaxoSmithKline