Global and ASEAN trends in Cellular Medicine:

Preparing for commercialisation

BioMalaysia August 2015

Tim Oldham PhD CEO, Cell Therapies Pty Ltd

Key themes

• Cell based therapeutics are coming of age and will transform healthcare

• Focus is turning to global deployment: scale-up and scale-out of a new industry is required

• Healthcare systems will need to adapt

Opportunities and challenges

for ASEAN

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Cell based therapeutics: transforming healthcare

Living human cells as therapeutics

60:40 autologous:allogeneic 20% CAGR

Regenerative medicine Cartilage repair for traumatic knee injury

Immunotherapy/gene therapy

90% complete remission of chemo refractory leukemia

β-thalassemia transfusion independence

Attracting significant investment

>$3b capital raise/deals pa including big pharma

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Current “generation” example #1: paediatric leukemia

• CAR-T (Chimeric Antigen Receptor T-cell) therapy

• Engineered T-cells (autologous)

• The worst kinds of childhood leukemia have been treated successfully

• Molecular remission: 90% complete response in ALL

• UPenn/Novartis: $250m investment in progress

• Juno Therapeutics: $175m Series A funding to develop MSK/ FHCC/Seattle Children’s technology $390m raised since

• Kite Pharma, Celgene, Pfizer, GSK, Lion Amgen, Bellicum, Autolus, Servier playing

10/30/13 Leukemia Patients Remain in Remission More Than Two Years After Receiving Genetically Engineered T Cell Therapy

www.uphs.upenn.edu/news/news_releases/2012/12/tcell/print.html 1/2

 

December  9,  2012

CONTACT:

Holly  Auer215-­349-­5659holly.auer@uphs.upenn.edu

This  release  is  available  online  athttp://www.uphs.upenn.edu/news/News_Releases/2012/12/tcell/

Leukemia  Patients  Remain  in  Remission  More  Than  Two  Years

After  Receiving  Genetically  Engineered  T  Cell  Therapy

University  of  Pennsylvania  Researchers  Report  on  Results  of  Trial  in  12  Patients,  Including  TwoChildren

ATLANTA  —  Nine  of  twelve  leukemia  patients  who  received  infusions  of  their  own  T  cells  after  the  cells  had  beengenetically  engineered  to  attack  the  patients’  tumors  responded  to  the  therapy,  which  was  pioneered  by  scientistsin  the  Perelman  School  of  Medicine  at  the  University  of  Pennsylvania.  Penn  Medicine  researchers  will  presentthe  latest  results  of  the  trial  today  at  the  American  Society  of  Hematology’s  Annual  Meeting  and  Exposition.

The  clinical  trial  participants,  all  of  whom  had  advanced  cancers,  included  10  adult  patients  with  chroniclymphocytic  leukemia  treated  at  the  Hospital  of  the  University  of  Pennsylvania  (HUP)  and  two  children  withacute  lymphoblastic  leukemia  treated  at  the  Children’s  Hospital  of  Philadelphia.  Two  of  the  first  three  patientstreated  with  the  protocol  at  HUP  –  whose  cases  were  detailed  in  the  New  England  Journal  of  Medicine  andScience  Translational  Medicine  in  August  2011  –  remain  healthy  and  in  full  remissions  more  than  two  years  aftertheir  treatment,  with  the  engineered  cells  still  circulating  in  their  bodies.  The  findings  reveal  the  first  successfuland  sustained  demonstration  of  the  use  of  gene  transfer  therapy  to  turn  the  body’s  own  immune  cells  intoweapons  aimed  at  cancerous  tumors.

―Our  results  show  that  chimeric  antigen  receptor  modified  T  cells  have  great  promise  to  improve  the  treatment  ofleukemia  and  lymphoma,‖  says  the  trial’s  leader,  Carl  June,  MD,  the  Richard  W.  Vague  Professor  inImmunotherapy  in  the  department  of  Pathology  and  Laboratory  Medicine  and  director  of  Translational  Researchin  Penn’s  Abramson  Cancer  Center.  ―It  is  possible  that  in  the  future,  this  approach  may  reduce  or  replace  theneed  for  bone  marrow  transplantation.‖

The  results  pave  the  way  for  a  potential  paradigm  shift  in  the  treatment  of  these  types  of  blood  cancers,  which  inadvanced  stages  have  the  possibility  of  a  cure  only  with  bone  marrow  transplants.  That  procedure  requires  alengthy  hospitalization  and  carries  at  least  a  20  percent  mortality  risk  -­-­  and  even  then  offers  only  a  limitedchance  of  cure  for  patients  whose  disease  has  not  responded  to  other  treatments.

Three  abstracts  about  the  new  research  will  be  presented  during  the  ASH  meeting.  David  Porter,  MD,  director  ofBlood  and  Marrow  Transplantation  in  the  Abramson  Cancer  Center,  will  give  an  oral  presentation  of  Abstract#717  on  Monday,  Dec.  10,  at  5  PM  in  the  Thomas  Murphy  Ballroom  4,  Level  5,  Building  B  of  the  Georgia  WorldCongress  Center.  Michael  Kalos,  PhD,  director  of  the  Translational  and  Correlative  Studies  Laboratory  at  Penn,will  give  an  oral  presentation  on  Abstract  #756  on  Monday,  Dec.  10,  at  5:45  PM  in  C208-­C210,  Level  2,  BuildingC.  Stephan  Grupp,  MD,  PhD,  director  of  Translational  Research  in  the  Center  for  Childhood  Cancer  Research  atthe  Children's  Hospital  of  Philadelphia,  will  present  a  poster  of  Abstract  #2604  on  Sunday,  Dec.  9,  at  6  PM  in  HallB1-­B2,  Level  1,  Building  B.

The  protocol  for  the  new  treatment  involves  removing  patients'  cells  through  an  apheresis  process  similar  toblood  donation,  and  modifying  them  in  Penn's  cell  and  vaccine  production  facility.  Scientists  there  reprogram  thepatients’  T  cells  to  target  tumor  cells  through  a  gene  modification  technique  using  a  HIV-­derived  lentivirus  vector.The  vector  encodes  an  antibody-­like  protein,  called  a  chimeric  antigen  receptor  (CAR),  which  is  expressed  on  thesurface  of  the  T  cells  and  designed  to  bind  to  a  protein  called  CD19.

The  modified  cells  are  then  infused  back  into  the  patient's  body  following  lymphodepleting  chemotherapy.  Oncethe  T  cells  start  expressing  the  CAR,  they  focus  all  of  their  killing  activity  on  cells  that  express  CD19,  whichincludes  CLL  and  ALL  tumor  cells,  and  normal  B  cells.  All  of  the  other  cells  in  the  patient  that  do  not  expressCD19  are  ignored  by  the  modified  T  cells,  which  limits  systemic  side  effects  typically  experienced  during

“I’ve told the team that resources are not an issue. Speed is the issue.” Novartis Chief Executive Joseph Jimenez

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Current “generation” example #2: beta-thalassemia

• Single treatment cure for beta-thalassemia

• Gene therapy

• Engineered HSC’s – blood stem cells (autologous)

• Transfusion independence within 2 weeks with latest version; 6 year duration of effect in early version

• Bluebird Bio raised $211m post announcement of these results

• Sangamo and others also playing

Bluebird bio Reports Rapid transfusion Independence in Beta-thalassemia Major Patients Treated with its LentiGlobin Product Candidate European Hematology Association Meeting, June 2014

Page 5

Potential becoming reality, big pharma in

Nobel Prize to Donnall Thomas (1990)

Understanding Mesengenic Lineage (1990s)

Organogenesis first regulatory approval for Apligraft ®(2005)

Osiris & Genzyme Deal $1.38 billion (2008)

Osiris fails Phase III study in GvHD (2009)

Cellerix fails Phase III study in anul fistula (2009)

Tigenix MAA (2009)

Athersys - Pfizer Deal (2009)

Osiris received marketing approval for Prochymal in Canada & NZ (May 2012)

Hospira & Kiadis Deal (2011)

Mesoblast & Cephalon Deal $1.7 billion (2011)

Dendreon BLA (2010) Shire acquires Pervasis Advanced Bio Healing assets (Apr 2012)

Organogenesis 2nd BLA Gintuit (March 2012)

1988 Systemix

1992 Geron

1997 FDA BLA for Genzyme’s Carticel

1999 Intercytex

Fibrocell BLA (2011)

TiGenix EU approval (2010)

2010 800 INDs at FDA >1m patients 50 Public companies >$6 Bil cap

Pro

ject

ed p

rod

uct

rev

enu

e in

nex

t 1

0 y

ears

Technology Trigger

Peak of Inflated Expectations

Trough of Disillusionment

Slope of Enlightenment

1997 FDA BLA for Apligraf

2000 Time cover

2001 3300 jobs, 73 firms >$2.56B cap

2001-2003 ATS • Organogenesis Chapter 11 • Genzyme downsizing • 9 tissue therapies fail at FDA • 500 lost jobs <$300M market cap

2006 Genzyme 10,000 Carticel

2005 CIRM

Teva and Gamida Cell enters into a Joint Venture (2006)

2007 200,000 Apligraf

Novartis licenses U Penn CAR (Aug 2012)

2012 Nobel Prize to Shinya Yamanaka and John Gurdon

>200 companies developing cell therapeutics

First generation Technology

>700 companies developing cell and tissue therapeutics

Good science leading the way

2011 Sanofi acquires Genzyme (Feb 2011)

Cook Group acquires General Biotechnology assets (Apr 2012)

Novartis acquires Dendreon facility (Dec 2012)

Smith & Nephew acquires Healthpoint (Nov 2012)

Mesoblast acquires Osiris MSC assets (Oct 2013)

MediPost KFDA approval for CartiStem (2012)

Bluebird bio – Celgene collaboration (2013)

EU approval Glybera (2012)

GSK license from Fondazione Telethon (2010)

Ostuka license Living Cell Technologies (Dec 2012)

Merck-Serono license Opexa Therapeutics (Mar 2013)

6

Juno $175m Series A (2013) $134m Series B (2014) $256m IPO (2014)

Bluebird bio IPO $116m (2013)

Dendreon Chapt 11 (2014)

Bellicum $140m IPO (2014)

Kite $140m IPO (2014)

Financing and deal momentum increasing

Source: Alliance for Regenerative Medicine, Q2 2015 Quarterly Data Report

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Wide therapeutic coverage by clinical trials

Page 8

Source: Alliance for Regenerative Medicine, Q2 2015 Quarterly Data Report

Key themes

• Cell based therapeutics are coming of age and will transform healthcare

• Focus is turning to global deployment: scale-up and scale-out of a new industry is required

• Healthcare systems will need to adapt

Opportunities and challenges

for ASEAN

Page 9

New, local distribution and delivery models needed

Drug/biologic Cell/tissue

Allogeneic Autologous

Starting material

Inert, stable, pure Living, complex, variable

Batch size Thousands to millions of

doses <1,000 doses 1 dose

Shelf-life 2-4 years Varies 24-48h

Storage/ transport

Room temp or 2-8 degC −196 degC (liquid nitrogen)

Scheduling of treatment

Independent of manufacturing

Care partnership: integrated JIT manufacture

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This is CTPL’s unique expertise. 1st movers

will become hubs.

Can be manufactured at massive scale in 1-2 global facilities

On the shelf when prescriber needs it

Prescriber initiates ‘needle-to-needle’ production process

Must be manufactured close to patient

Hypothetical CAR-T ‘needle-to-needle” chain

Source: Cytotherapy 2013 Nov 15 (11), 1406-1415

Patient in Thailand • What patient screening

required in TH, MY, AU? • Which apheresis centres

can reliably conduct a complex MNC collection and maintain control (identify sites)?

Cryopreservation in Malaysia pending manufacturing instruction

• What if patient has infectious disease (Hep C)? • Cryo-protectant includes HSA and is not available

in Malaysia – can it be imported? How?

Viral vector imported from US

• Gene modified organism

Manufacturing in Australia • Gene modified organism

Final product shipped to patient

• Stored in LN2 • Thawing protocol?

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Capacity scenarios: gene-modified cells

Scale up scenarios: gene modified/ immunotherapies

Clinical production Commercial production

Current paradigm “Autologous Production for the Future”

Demand (pax pa) 10’s 1,000’s 1,000’s

Throughput/BSC/shift 40 pa 40 pa 150 pa

FTE/BSC (/100 pax) 4.5-6 (11-15) 3-4 (5-6) 1-2 (0.7-1)

BSC equivalents 1-2 100-200 30-50

FTE equivalents 9-12 300-800 30-80

COGS (ex consumable) $60k $40-50k <$20k

COGS (all in) >$100k ~$100k $15-20k

ILLUSTRATIVE

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Capacity scenarios: gene-modified cells

Scale up scenarios: gene modified/ immunotherapies

Clinical production Commercial production

Current paradigm “Autologous Production for the Future”

Demand (pax pa) 10’s 1,000’s 1,000’s

Throughput/BSC/shift 40 pa 40 pa 150 pa

FTE/BSC (/100 pax) 4.5-6 (11-15) 3-4 (5-6) 1-2 (0.7-1)

BSC equivalents 1-2 100-200 30-50

FTE equivalents 9-12 300-800 30-80

COGS (ex consumable) $60k $40-50k <$20k

COGS (all in) >$100k ~$100k $15-20k

ILLUSTRATIVE

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LVV 19%

Materials and reagents

28%

Facilities 8%

Labour 20%

QC/release assays 25%

Manufacturing costs: manual process at scale 100% = $50-90k

Sponsor COGS drivers: manual gene modified cellular therapy

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Achieving a notional

target COGS <$30k

requires 65% reduction

Release testing, reagents

and consumables, and

facility costs including

labour contribute

approximately equally

to total product costs

Cost reduction solutions

must address all three

areas

Source: Disguised client example

COGS improvement opportunity summary

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Manual processat scale

Apheresis sitemanagement

Next Genprocessing

Alternate cellselection

QC assay costreduction

QC assayinnovation

Eliminate 2ndapheresis

Target process

Sponsor cost

$ per patient

Processing

Vector

Logistics Future Gen processing

Source: Disguised client example

Key themes

• Cell based therapeutics are coming of age and will transform healthcare

• Focus is turning to global deployment: scale-up and scale-out of a new industry is required

• Healthcare systems will need to adapt

Opportunities and challenges

for ASEAN

Page 16

COGS improvement opportunity summary

Page 17

Manual processat scale

Apheresis sitemanagement

Next Genprocessing

AlternateCD34+

selection

QC assay costreduction

QC assayinnovation

Eliminate 2ndapheresis

Target process

Manual processat scale

Apheresis sitemanagement

Next Genprocessing

Alternate cellselection

QC assay costreduction

QC assayinnovation

Eliminate 2ndapheresis

Target process

Sponsor cost

Clinical site cost $ per patient

Processing

Vector

Logistics

Apheresis

Transplant

Future Gen processing

Source: Disguised client example

Deployment strategy is influenced by multiple stakeholders

What deployment strategy?

Regulator: how is reproducibility, consistency and

safety assured? Is promotion appropriate? Drug or practice

of medicine?

Payor: is the product cost effective relative to standard of

care? Are the associated procedures funded? Pay for

performance?

User: does this interrupt my current treatment/referral

flows and revenue? Do I know enough to use this safely?

Logistics: what is incoming and outgoing product shelf-life? Is

there a cryo-protected hold step? Does clinical site have

capabilities

Commercial access: how do I maximize patients who can be

treated (and donations that can be accepted into production)?

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Current Stem Cell Transplant (SCT) capability requires development

Page 19

Thailand

120 -150 stem cell transplant performed per year (majority from 10% population covered by civil servant benefit scheme)

~50% autologous; remainder sibling donor

Programs - Allogeneic SCT for thalassemia and blood malignancies and Autologous SCT for lymphoma and multiple myeloma

Four centers – all specialized hospitals at peak of the referral chain

Sepsis 4.5% of SCT deaths (Australia 1%)

Malaysia

• 265 stem cell transplant performed per year

• ~33% are autologous; remainder sibling donor

• Four major centers for autologous SCT

• 100d survival 84% (US >90% for related donor)

• One year survival ~75% (US >90% for related donor)

• Infection/sepsis 17%/5% of SCT deaths (US 7%/1%)

500-2,000 patients pa potential demand for a gene therapy for beta-thalassemia or a CD19 CAR-T therapy for leukemia

• Significant apheresis and transplant unit capacity build required (beds, staff, equipment)

• Significant improvements in access (funding) will be required • Lower SCT survival rate – reputational risk/risk management issue?

Key themes

• Cell based therapeutics are coming of age and will transform healthcare

• Focus is turning to global deployment: scale-up and scale-out of a new industry is required

• Healthcare systems will need to adapt

Opportunities and challenges

for ASEAN

Page 20

Opportunities and challenges for ASEAN

Opportunities Challenges

Regulation

Clinical infrastructure

Funding

Advertising and promotion

Clinical trials

High tech manufacturing hub

Breakthrough treatment

Clinical infrastructure

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CTPL: providing the infrastructure to enable a new industry

22

Home base - Melbourne Peter Mac Cancer

Centre

Research and translation - Adelaide

Nextcell at CRC for Cell Therapy Manufacturing

PharmaBio - Nagoya Strategic Alliance Future - Malaysia

“Autologous Production for the Future” facility

• Commercial facility • Multi-client user • <10h flight from Dubai,

Seoul, Melbourne

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