CSL Ltd. — Investor Presentation 2002

Dec 12, 2002

ASX ANNOUNCEMENT

CSL PRESENTS ANNUAL REVIEW OF R&D

Dr Andrew Cuthbertson, CSL's R&D Director, and Dr Russell Basser, CSL's Global Director of Clinical Development, are today presenting the annual overview of CSL's
research and development portfolio.

Attached are copies of the slides to be presented.

Peter/Furvey COMPANY SECRETARY

13 December 2002

67 Pages following:

Phone: 461 3 9389 1911

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CSL Limited (ABN 99 051 588 348) 45 Poplar Road Parkville Victoria 3052 Australia Fax: +61 3 9387 8454

"CSL R&D INVESTMENT"

December 2002

OSL Limited

OVERVIEW

R&D Investment Ppocess Future Value Drivers - HPV Merck Update - Haemostatic Dressing - PHDL and stroke - ISCOM® Adjuvant leverage $- HCV$ . CerVax16 and AIN · ESO1 and cancer

T.

Times Strategie

• Biotech therapy for blindness

HUMAN HEALTH R&D

Parkville

Broadmeadows

PORTFOLIO MANAGEMENT STRUCTURE

PharmaPlan

Sirdizey & Investment

Naw Opportunities

Identification Evaluation Residde

Project Management

Operations Finghold Sirciecy

Project Review

Renformance

Deal Making

HPV VACCINE

6 Merck worldwide Phase ITIT Program under way - Australian site Pecruitnent

GERVICAL CANGER: (Human Papillomavirus Infection)

Significant Medical Need

• 6 FPV causes cervical cancer
• 0 470,000 cases of cervical cancer annually worldwide
• Second leading cause of cancer-related deaths Darridy (1911) 35-55 year olds
• 11 U.S. 50% of cervical cancers occur in partients gganasy
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• 50 million adolescents and adult females at risk
  • $\sim$ 25% of female adolescents are infected by
  • first year in college¹
  • ~50% of females age 23-27 years are Mezerze

-Burk, et al. JID, Vol. 174, 1996; ?Peyton et al. J Inf Dis 2001 183: 1554-64

HUMAN PAPILLOMA VACCINE: Phase III Program Underway

Phase III quadrivalent vaccine program Designation E Recombinant virus-like particles

$-$ (Types 6, 11, 16, 18)

Z.

• HPV 16 and 18 associated with most cancer deaths

Phase II Proof-of-Concept Study with HPV 16 vaccine

HPV INTELLECTUAL PROPERTY

CSL has licensed Merck exclusively a portfolio of intellectual properly.

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• A patent has already been granted to CSL in Australia claiming a method of manufacturing a VLP/HPV vaccine and the vaccine ffself.
• The European Pattent Office has published tis intention to grant T a European patent to CSL covering certain relevant serotypes.
• In relation to one patent application in the US, an interference anang procedure is pending. As the senior party, CSL has the earliest filing derie.
• Other relevant US patent applications are still in the process of being examined.
• Merck has confirmed that it is confident that any intellectual property issues will not delay its HPV program.

The New England Journal of Medicine

Copyright © 2002 by the Massachusetts Medical Society

VOLUME 347

NOVEMBER 21, 2002

NUMBER 21

A CONTROLLED TRIAL OF A HUMAN PAPILLOMAVIRUS TYPE 16 VACCINE

LAURA A. KOUTSKY, PH.D., KEVIN A. AULT, M.D., COSETTE M. WHEELER, PH.D., DARRON R. BROWN, M.D., ELIAV BARR, M.D., FRANCES B. ALVAREZ, R.N., LISA M. CHIACCHIERINI, PH.D., AND KATHRIN U. JANSEN, PH.D., FOR THE PROOF OF PRINCIPLE STUDY INVESTIGATORS

HUMAN PAPTLLOMA VACCINE: Proof-of-Concept Efficacy Study

Incidence of Viral Infection and Cervical Intraepithelial Neoplasia (CINs)

Enclooter	Placebo $C_6$ $C_5$	EDVE (6) Vcccine $C$ 0525	Vaccine Enlead
HPV 16 Infection and CIN	46	0	100%
FPV infection	82	0	100%
CIN Grade 1	$\overline{\phantom{a}}$	6	100%
GIN Grade 2/3	なり	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 decith 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 donormal Papanicolaou smears would remove a substantial burden from the health care system."

NEW HTGH VALUE PRODUCTS FROM PLAMSA

O Haemostatic Dressing (Fibrin Bandage) O Reconsilities High Density Lipoprotein (rHDL)

HAEMOSTATIC DRESSING

O Features: - Rapielly stops significant bleeding - Fully degradable in stitu (natural proteins)

HAEMOSTATIC DRESSING

Structure

$2$ ad fibrinogen layer Thrombin Teyyer

reabsorbable grid

1st fibrinogen layer

HAEMOSTATIC DRESSING

O Close collaboration with Anerican Red Gross O IND successfully lodged with $FD/4$ O Commencement formal Phase I/III studies on track mid-2003

RECONSTITUTED HIGH DENSITY LIPOPROTEIN (7HDL)

O HDL: "good cholesterol", Mops up cholesterol, excreted through liver

Apolipoprotein A-I purified from unused plasma fractions

O Reconstituted with lipid = rHDL

• 8 Additional value from plasma
• O IP on process and indications

RECONSTITUTED HDL

o Development indication STROKE

O New PCT preclinical data O International EXPERT Panel

PHDL FOR STROKE

STROKE

• When blood cannot get to the brain = blockage (80%), bleeding (15%), other Diffeone
• decith Brd commonest cause in developed countries
• long term disability leading cause
  • · ~50% people dependent afterwards
  • · regulies assistance at home / nursing home

THE NUMBERS

O. USA – 750,000 strokes per year - 150,000 deaths per year O ALSTROITO – 25,000 strokes per year 5,000 deaths per year

CURRENT TREATMENT

Clot dissolving agent (tPA) - given to only 5% patients

F nust be given early, associated risk of bleeding

Blood fhinning ngang

Designation

Z.

$\sqrt[n]{2}$ iroke unit"

Rehabilitation 6 (Prevention)

PRODUCT PROPOSITION

• Reduce tissue damage in the brain after a stroke O Potential benefits - increase independence - reduction in need for rehabilitation, nursing home

EVIDENCE IN SUPPORT

Preclinical

Type of the contract of the contract of the contract of the contract of the contract of the contract of the c

• multiple properties in vitro and in vivo Consistent with tissue protection

• reduction in stroke dancye in rats (2 laboratories)

• Glinigal
• trials in ~150 people (non-stroke)
• Very safe
• biologically active

TREATMENT OF STROKE IN RAT MODEL

stroke + rHDL

With permission: D Howells et al, 2002

PROGRESS

o Preclinical work ongoing Enternational expert panel meeting Nov 2002 - excited by datas eager to test clinically E clear clinical path outlined

$\sum$

LEVERAGING ISCOM® TECHNOLOGY

o Proprietary Adjuvant Technology O Integrated Immune Response o Inportance of T-cells o Therapy for Infectious Diseases and Gancer O. Process Optimisation o Registrable

ISCOM® ADJUVANT PRODUCTS

HCV GerVax16 ESO-1

HOV-THE DISEASE

o Viral infection o 85% become chronic carriers Causes chronic liver disease P O Conditions - carrier - cirrhosis - liver cancer in about 5%

THE NUMBERS

• 170 million people infected worldwide
• 3 million infected
• ~10,000 decihs per year
• DE AUSTROITO

· USA

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• ~200,000 infected
• 10,000 new cases per year

CURRENT TREATMENT

O Interferon + ribovirin O Clears virus in ~40% - efficacy depends on type of HCV O Lots of side effects o Expensive

PRODUCT PROPOSITION

O Proprietary Chiron antigens plus CSL ISCOM® adjuvant O Induce immunity to HCV

Clear virus -> prevent further liver damage O Improve effectiveness of current Fredineni

EVIDENCE

6 Preclinical - long lasting cellular immunity $O$ Clinical

• currently testing safety and immunity in volunteers

HOV VACCINE in Rhesus Macaque Monkeys - DURATION OF CELLULAR IMMUNITY

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

PROGRESS

o Safety & immunity study with test protein o Further safety test planned 2nd half 2003 - HCV infected parients

HUMAN PAPILLOMA VIRUS (HPV) THERAPY CERVAX 16

AIN-THEDISEASE

• Persistent HPV infection causes:
• cervical dysplasta -> cancer
• & anal dysplasta > cancer
• orher genital diseases and cancer
• (non-genital disease and cancer)
• Sexually transmitted

$\sum$

$\overline{\phantom{a}}$

• Screening important in detection of dysplasta
• ie Pap smears for cervical abhormalities

ANAL DYSPLASTA -THE NUMBERS

Only recently identified as major health $\Box$ Droblem Especially gay nales (& fencles) - high indidence dysplasta and cancer 0 USA ~180,000 new cases per yr

CURRENT TREATMENT o Local destruction - Surgery - Freezing - burning o High recurrence O Side effects

CSL PRODUCT

O ESCOM® / HPV fusion DPOTEIN (E6E7) o Issued U.S. IP on all components

PRODUCT PROPOSITION

• Induce immunity to HPV $\bigcirc$ - cellular and antibody Clear virus -> healing of dysplasia ana any
  K - reduce the need for destructive Tractment

= reduce risk of developing cancer

EVIDENCE

o Preclinical - in mice - prevents HPV-related cancer from growing A shrinks established HPV-related cancer O Chateal Daase 1 stucky - sefe, well tolereted - induces desired immunity

TREATMENT OF HPV CANCER IN WICE

A randomised placebo controlled trial of $CERVAX^{TM}$ 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

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

PROGRESS

Currently - further testing for optimal dose & Stanzallia

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Literatur

Discussing gnal dysplasta study with National Centre in HIV Epiclemiology and Clinical Research

ESO1 CANGER ANTIGEN FOR MELANOMA: Ludwig Institute collaboration

THE DISEASES

0 NY-ESO1 is a cancer-related protein = only rarely on normal fissues

O Found on many cancers - melanoma ~35% of cases - lesser extent: bladder, lung, breast, prostrite, others

MELANOMA - THE NUMBERS

USA - 51,000 new cases per year - 7,800 decims Australia - 8,500 new cases per year $-1,000$ deaths

CURRENT TREATMENT FOR MELANOMA

O surgery Ourcollotherapy O Interferon o chemotherapy O (prevention)

CSL PRODUCT

O NY-ESO1 protein /
TSCOM® Adjuvant

PRODUCT PROPOSITION

• Theluce immunity to NY-ESO1
• cellular and antibody
• Stinukite inmune system to destroy cancer $\sum$ $C2$ $S$
• Clinical goals e de la provincia de la construcción de la construcción de la construcción de la construcción de la construcci
  Construcción de la construcción de la construcción de la construcción de la construcción de la construcción de

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$-$ shrink established metastatic melanoma $\rightarrow$ prolong life

• mop up invisible remaining cancer cells after surgery in localised melanoma -> Increase aure rate

PROGRESS

O Preclinical - cellular and humoral immunity

Chateal

• phase 1 study completed with Ludwig Institute for Concer Research, Melbourne $-$ sqf2
• dear induction of cellular immunity

Rroof-of-concept irich in nelanome with Ludwig Enstitute in discussion for 2008

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, Heidelberg, Australia, Simon Green, Andrew Cuthbertson, Darryl Maher, David Ryan, Michael 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

O Big unmet need O Flinders University IP OZAWD O Glaucoma O Uveitis, correal 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. MAVRANGELOST, H. ZOLAT, S. TAYLORE, A. YUSIMF & K. A. WILLIAMS* *Department of Ophthalmology, Flinders University of South Australia, Adelaide, † Child Health Research Institutie, Adelaide and FGSL Research and Development, Melbourne, Australia

Clin Exp Immunol 2002; 12367-74

PRODUCT PROPOSITION

O Topically delivered recombinant antibocly Therapy for treating serious eye diseases

EXPANDING CURRENT BUSINESS

• Influenza Vaccine Thionersal-free en de la provincia de la construcción de la construcción de la construcción de la construcción de la construcc
  Construcción de la construcción de la construcción de la construcción de la construcción de la construcción de

• Premium products

• IVIGS - nano, liquid, CSL/ZLB - Rhophylac

TNTRAVENOUS IMMUNOGLOBULINS Confinuous improvement of key product Worldwide first nanofiltered IVIG (Early 2003) 0 12 g formet eveileble in USA Liquid formulation (12%) with improved burity (2004) O Liquid state of the art product using combined ZLB/CSL technology (2006) -aualfry-yield-capacity

RHOPHYLAC (Plasma Derived Anti-D)

• Features Terminal - Purity, yield 5 Indications EIDN
• O Anticipated Indications
• ITP in adults and children
• US Registration
  • - Submission accepted 2002
  • E Launch 2004

CSL R&D LEVERAGE

o Access and add value to IP D Novel immunotherapeuties based on ISCOM® adjuvant technology 5 World class plasma products