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					 “CSL R&D INVESTMENT”




December 2002

            CSL Limited
                OVERVIEW
l   R&D Investment Process
l   Future Value Drivers
     – HPV Merck Update
     – Haemostatic Dressing
     – rHDL and stroke
     – ISCOM® Adjuvant leverage
       • HCV
       • CerVax16 and AIN
       • ESO1 and cancer
    – Biotech therapy for blindness
        HUMAN HEALTH R&D




Parkville   Broadmeadows   Bern
        PORTFOLIO MANAGEMENT
              STRUCTURE
                         PharmaPlan


                    Strategy & Investment




    New            Project            Project
Opportunities                                   Commercial
                 Management           Review

Identification
                 Operations      Performance    Deal Making
  Evaluation
                  Financial
   Testing
                  Strategy
            HPV VACCINE


l   Merck worldwide Phase
    III Program under way
     – Australian site
       recruitment
                       CERVICAL CANCER:
                  (Human Papillomavirus Infection)
   Significant Medical Need

   l         HPV causes cervical cancer
   l         470,000 cases of cervical cancer annually worldwide
                – Second leading cause of cancer-related deaths
                  particularly 35-55 year olds
   l         In U.S. 50% of cervical cancers occur in patients
             screened
   l         50 million adolescents and adult females at risk
                – ~25% of female adolescents are infected by
                  first year in college1
                – ~50% of females age 23-27 years are
                  infected2
1Burk,   et al JID, Vol 174, 1996; 2Peyton et al. J Inf Dis 2001;183: 1554-64
HUMAN PAPILLOMA VACCINE :
    Phase III Program Underway
l   Phase III quadrivalent vaccine program
     – Recombinant virus-like particles
        • (Types 6, 11, 16, 18)
     – HPV 16 and 18 associated with most
       cancer deaths
l   Phase II Proof-of-Concept Study with HPV
    16 vaccine
    HPV INTELLECTUAL PROPERTY
l   CSL has licensed Merck exclusively a portfolio of intellectual
    property.
l   A patent has already been granted to CSL in Australia claiming a
    method of manufacturing a VLP/HPV vaccine and the vaccine
    itself.
l   The European Patent Office has published its intention to grant
    a European patent to CSL covering certain relevant serotypes.
l   In relation to one patent application in the US, an interference
    procedure is pending. As the senior party, CSL has the earliest
    filing date.
l   Other relevant US patent applications are still in the process of
    being examined.
l   Merck has confirmed that it is confident that any intellectual
    property issues will not delay its HPV program.
HUMAN PAPILLOMA VACCINE:
   Proof-of-Concept Efficacy Study
      Incidence of Viral Infection and
   Cervical Intraepithelial Neoplasia (CINs)
                                     HPV 16
                           Placebo   Vaccine   Vaccine
        Endpoint            Cases     Cases    Efficacy
HPV 16 Infection and CIN     41        0        100%
HPV infection                32        0        100%
CIN Grade 1                   5        0        100%
CIN Grade 2/3                 4        0        100%
 ACCOMPANYING EDITORIAL
“The Beginning of the End for Cervical Cancer?”
         by Christopher P. Crum, M.D.
“Because the more pernicious cancers appear most often
with HPV-16 and HPV-18, the level of protection from
death due to cervical cancer could exceed 95 percent.”


“Although it is premature to calculate the cost-benefit
ratio of HPV vaccination, a program that both prevented
cancer and reduced the frequency of abnormal
Papanicolaou smears would remove a substantial burden
from the health care system.”
    NEW HIGH VALUE PRODUCTS
         FROM PLAMSA

l Haemostatic Dressing
  (Fibrin Bandage)
l Reconstituted High Density
  Lipoprotein (rHDL)
     HAEMOSTATIC DRESSING


l   Features:
     – Rapidly stops significant
       bleeding
     – Fully degradable in situ
       (natural proteins)
   HAEMOSTATIC DRESSING

Structure
                    2nd
                    fibrinogen
                    layer
                    thrombin
                    layer

  reabsorbable       1st fibrinogen
  grid               layer
     HAEMOSTATIC DRESSING
                Mode of action:
Solubilisation of the components after wetting by
                   blood contact

                 thrombin
 fibrinogen                        fibrin



                             fibrin polymer
                              (“blood clot“)
    HAEMOSTATIC DRESSING

l Close collaboration with
  American Red Cross
l IND successfully lodged with
  FDA
l Commencement formal Phase
  I/II studies on track mid-2003
RECONSTITUTED HIGH DENSITY
     LIPOPROTEIN (rHDL)

l   HDL: “good cholesterol”. Mops up
    cholesterol, excreted through liver
l   Apolipoprotein A-I purified from unused
    plasma fractions
l   Reconstituted with lipid - rHDL
l   Additional value from plasma
l   IP on process and indications
       RECONSTITUTED HDL

l Development        7
                               Cortex7                 Striatum
  indication         6                        6




  STROKE
                     5                        5


                     4                        4


l New rat            3                        3



  preclinical data   2                        2




l International
                     1                        1


                     0                        0


  expert panel
                         1.20 -0.92   -4.80       1.20 -0.92 -2.80
rHDL FOR STROKE
                    STROKE
l   When blood cannot get to the brain
     – blockage (80%), bleeding (15%), other
l   Outcome
     – death - 3rd commonest cause in developed
       countries
     – long term disability - leading cause
        • ~50% people dependent afterwards
        • require assistance at home / nursing home
      THE NUMBERS

l USA
   – 750,000 strokes per year
   – 150,000 deaths per year
l Australia
   – 25,000 strokes per year
   – 5,000 deaths per year
        CURRENT TREATMENT
l   Clot dissolving agent (tPA)
     – given to only 5% patients
     – must be given early, associated risk of
       bleeding
l   Blood thinning
l   “Stroke unit”
l   Rehabilitation
l   (Prevention)
     PRODUCT PROPOSITION

l Reduce tissue damage in the brain after
  a stroke
l Potential benefits
   – increase independence
   – reduction in need for rehabilitation,
     nursing home
        EVIDENCE IN SUPPORT
l   Preclinical
     – multiple properties in vitro and in vivo
        consistent with tissue protection
     – reduction in stroke damage in rats (2
        laboratories)
l   Clinical
     – trials in ~150 people (non-stroke)
     – very safe
     – biologically active
  TREATMENT OF STROKE IN
        RAT MODEL
 control stroke                          stroke + rHDL




With permission: D Howells et al, 2002
              PROGRESS

l Preclinical work ongoing
l International expert panel meeting Nov
  2002
   – excited by data: eager to test
     clinically
   – clear clinical path outlined
        LEVERAGING ISCOM®
           TECHNOLOGY
l   Proprietary Adjuvant Technology
l   Integrated Immune Response
l   Importance of T-cells
l   Therapy for Infectious Diseases
    and Cancer
l   Process Optimisation
l   Registrable
     ISCOM® ADJUVANT
         PRODUCTS

HCV
CerVax16
ESO-1
          HCV - THE DISEASE
l   Viral infection
l   85% become chronic carriers
l   Causes chronic liver disease
l   Conditions
     – carrier
     – cirrhosis
     – liver cancer in about 5%
              THE NUMBERS
l   170 million people infected worldwide
l   USA
     – 3 million infected
     – ~10,000 deaths per year
l   Australia
     – ~200,000 infected
     – 10,000 new cases per year
      CURRENT TREATMENT

l   Interferon + ribovirin
l   Clears virus in ~40%
     – efficacy depends on type of HCV
l   Lots of side effects
l   Expensive
    PRODUCT PROPOSITION
l Proprietary Chiron antigens plus CSL
  ISCOM® adjuvant
l Induce immunity to HCV


l Clear virus ® prevent further liver
  damage
l Improve effectiveness of current
  treatment
            EVIDENCE


l Preclinical
   – long lasting cellular immunity
l Clinical
   – currently testing safety and
     immunity in volunteers
HCV VACCINE in Rhesus Macaque Monkeys
- DURATION OF CELLULAR IMMUNITY

            100

            80
  % lysis




            60
                                                                 Core ISCOM
                                                                 RVV Core/E1
            40


            20


             0                         NT         NT        NT   NT = not tested
                   4          14            18   45    51

                            Weeks post last dose

  Polakos, N. et al. (2001) J. Immunol 166:
  3589-3598
           PROGRESS


l Safety & immunity study with
  test protein
l Further safety test planned 2nd
  half 2003
   – HCV infected patients
HUMAN PAPILLOMA VIRUS
    (HPV) THERAPY
      CERVAX 16
        AIN - THE DISEASE

l   Persistent HPV infection causes;
     – cervical dysplasia ® cancer
     – anal dysplasia ® cancer
     – other genital diseases and cancer
     – (non-genital disease and cancer)
l   Sexually transmitted
l   Screening important in detection of
    dysplasia
     – ie Pap smears for cervical
       abnormalities
         ANAL DYSPLASIA -
           THE NUMBERS

l   Only recently identified as major health
    problem
l   Especially gay males (& females)
     – high incidence dysplasia and cancer
l   USA ~180,000 new cases per yr
 CURRENT TREATMENT
l Local destruction
   – surgery
   – freezing
   – burning
l High recurrence
l Side effects
          CSL PRODUCT


l   ISCOM® / HPV fusion
    protein (E6E7)
l   Issued U.S. IP on all
    components
       PRODUCT PROPOSITION

l   Induce immunity to HPV
     – cellular and antibody
l   Clear virus ® healing of dysplasia
     – reduce the need for destructive
       treatment
     – reduce risk of developing cancer
                 EVIDENCE
l   Preclinical - in mice
     – prevents HPV-related cancer from growing
     – shrinks established HPV-related cancer
l   Clinical - phase 1 study
     – safe, well tolerated
     – induces desired immunity
  TREATMENT OF HPV CANCER
         IN MICE
             100
             90
             80
             70
             60
% alive at
             50
2 months     40
             30
             20
             10
              0
                   buffer    IMX     E6E7    CerVax
                             alone   alone
    CSL data on file, 2002
A randomised placebo controlled trial of
CERVAXTM 16, an immunotherapy for CIN,
demonstrating vaccine-induced immunogenicity
and possible reduction in tissue HPV viral load


  Frazer I.H.1, Quinn M.2, Nicklin J.3, Tan J.2, Perrin L.3, Ng P.4,
  O’Connor V.5, White O.1, Wendt N.1, Martin J.1, Mitchell S.V.6
  McKenzie A.6, Crowley J.6, Edwards S.6, Maher D.6


  1
   Centre for Immunology and Cancer Research, The University of
  Queensland, Princess Alexandra Hospital, Brisbane,
  Queensland; 2Royal Women’s Hospital, Parkville, Victoria;
  3                                               4
   Royal Women’s Hospital, Brisbane, Queensland; Mater
                                           5
  Mother’s Hospital, Brisbane, Queensland; Queen Elizabeth II
                                         6
  Jubilee Hospital, Brisbane, Queensland; CSL Limited, Parkville,
  Victoria, Australia.
                  PROGRESS


l   Currently - further testing for optimal dose &
    schedule

l   Discussing anal dysplasia study with National
    Centre in HIV Epidemiology and Clinical
    Research
ESO1 CANCER ANTIGEN FOR
       MELANOMA:
 Ludwig Institute collaboration
             THE DISEASES

l   NY-ESO1 is a cancer-related protein
     – only rarely on normal tissues

l   Found on many cancers
     – melanoma ~35% of cases
     – lesser extent: bladder, lung, breast,
       prostate, others
MELANOMA - THE NUMBERS

  l   USA
       – 51,000 new cases per year
       – 7,800 deaths
  l   Australia
       – 8,500 new cases per year
       – 1,000 deaths
CURRENT TREATMENT FOR
      MELANOMA
 l   surgery
 l   radiotherapy
 l   interferon
 l   chemotherapy
 l   (prevention)
      CSL PRODUCT


l   NY-ESO1 protein /
    ISCOM® Adjuvant
       PRODUCT PROPOSITION
l   Induce immunity to NY-ESO1
     – cellular and antibody
l   Stimulate immune system to destroy cancer
    cells
l   Clinical goals
     – shrink established metastatic melanoma ®
        prolong life
     – mop up invisible remaining cancer cells
        after surgery in localised melanoma ®
        increase cure rate
                PROGRESS
l   Preclinical
     – cellular and humoral immunity

l   Clinical
     – phase 1 study completed with Ludwig
        Institute for Cancer Research, Melbourne
     – safe
     – clear induction of cellular immunity

l   Proof-of-concept trial in melanoma with
    Ludwig Institute in discussion for 2003
   A phase I study of NY-ESO-1 ISCOMS in patients with
   NY-ESO-1 positive cancers and minimal residual
   disease

Jonathan S. Cebon, Ian D Davis, Phillip Parente, Mark Shackleton, Wendie Hopkins, Heather
Goldie, Eugene Maraskovsky, Weisan Chen, Qiyuan Chen, Heather Jackson, Ludwig Institute
for Cancer Research, Heidelberg, Australia, Grant McArthur, Peter MacCallum Cancer Institute,
Melbourne, Australia, Duncan MacGregor, Sue Sturrock, Austin & Repatriation Medical Centre,
                                             Cuthbertson,
Heidelberg, Australia, Simon Green, Andrew Cuthbertson, Darryl Maher, David Ryan, Michael
                                Miloradovic,
McNamara, Debbie Drane, Lena Miloradovic, CSL Limited, Melbourne, Australia, Gerd Ritter,
Lisa Stockert, Yao T Chen, Eric Hoffman, Lloyd Old, Ludwig Institute for Cancer Research, NY,
NY.
TOPICAL BIOTECH TREATMENT
        BLINDNESS
l   Big unmet need
l   Flinders
    University IP
l   AMD
l   Glaucoma
l   Uveitis, corneal
    graft rejection
     FLINDERS MEDICAL CENTRE
           PUBLICATION
“Penetration of engineered antibody
   fragments into the eye”
M. A. THIEL*, D. J. COSTER*, S. D. STANDFIELD*, H. M.
     BRERETON*, C. MAVRANGELOS†, H. ZOLA†, S. TAYLOR‡,
A. YUSIM‡ & K. A. WILLIAMS* *Department of Ophthalmology,
     Flinders University of South Australia, Adelaide,
†Child Health Research Institute, Adelaide and ‡CSL Research and
     Development, Melbourne, Australia

Clin Exp Immunol 2002; 128:67–74
      PRODUCT PROPOSITION


l   Topically delivered
    recombinant antibody
    therapy for treating serious
    eye diseases
       EXPANDING
    CURRENT BUSINESS

– Influenza Vaccine
  • Thiomersal-free
  • Premium products
– IVIGs - nano, liquid, CSL/ZLB
– Rhophylac
          INTRAVENOUS
        IMMUNOGLOBULINS
Continuous improvement of key product
l Worldwide first nanofiltered IVIG
   (Early 2003)
l 12 g format available in USA
l Liquid formulation (12%) with improved
   purity (2004)
l   Liquid state of the art product using
    combined ZLB/CSL technology (2006) --
    quality-yield-capacity
             RHOPHYLAC
       (Plasma Derived Anti-D)
l   Features
     – Purity, yield
l   Indications
     – HDN
l   Anticipated Indications
     – ITP in adults and children
l   US Registration
     – Submission accepted 2002
     – Launch 2004
        CSL R&D LEVERAGE

l   Access and add value to IP
l   Novel immunotherapeutics
    based on ISCOM® adjuvant
    technology
l   World class plasma products

				
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