CSL Ltd. — Investor Presentation 2008

Dec 10, 2008

R&D Briefing December 11, 2008

Agenda December 2008 R&D Briefing

• Sign in and coffee

• • Welcome Mark Dehring

• • Introduction and Highlights Andrew Cuthbertson

• • ‘Flu Vaccine Update

• • Plasma Replacement Therapies Stefan Schulte

• • rCoagulation Products

• • Q&A Andrew Cuthbertson

• • Break

• • ISCOMATRIX® Adjuvant Andrew Cuthbertson Therapeutic Proteins Overview

• • Pre-clinical /Early Clinical Projects Andrew Nash

• • Earlier Research Projects

• • Summary Highlights, Q&A and Wrap Up Andrew Cuthbertson

R&D Strategy

• Maintain commitment

to extracting maximum value from existing assets and supporting and improving current products

• Develop new protein-based therapies for treating serious illnesses focusing on products that align with our technical and commercial capabilities

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R&D Core Capabilities and Focus Areas

• Protein Replacement Immuno-modulators Therapeutic Proteins

• Therapies (ISCOMATRIX[®] ) •

• • • Haemostasis/ Critical rMAbs Prophylactic vaccines Care products • Cytokines and

• • Immunoglobulins receptors • •

• • Albumin fusion Cell surface targets Extend partnerships • to therapeutic

• technology - T1/2 Specialized treatment vaccines

• • Other plasma areas therapies

New Frontiers

• Emerging biological science

• Expertise in complex biological medicines

4

Leveraging Global Capabilities

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CSL Bio- CSL CSL Bio-
CSL Behring
plasma Limited therapies
Organization by site
Marburg Bern K3 KoP Japan Broad- Parkville Parkville
meadows
Global project management to ensure access to best capabilities
Integration via project management process
Organization by function
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5

Global R&D Pipeline

December 07

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CSL718 Humate ® P
SCIg 20%
Zemaira ® US
Privigen®
IVIG 10%
GARDASIL®
Berinert ® Rhophylac ® ITP
US
Zemaira® EU Beriplex ® EU
Fluvax ® China
Afluria ® US
Afluria/Enzira® EU
Rec coag factors Rec coag factors Vaccines– Merck
Novel plasma
proteins Vaccines– Merck Partnered Vaccine
Programs
Vaccines– Merck
Vaccines– Wyeth
CSL412
Vaccines – Wyeth
CSL444 ISCOMATRIX® Flu
Beta common Pandemic
(Bion1/2) ISCOMATRIX® Flu
CAM3001 CSL401
CSL111 GM-CSFR - Pandemic Flu
reconstituted HDL CAT/AZ
Discovery projects
MK6105 IL-13R
Merck
CSL360 for AML
Core Capabilities Plasma Therapeutics Vaccines ISCOMATRIX® Adjuvant Recombinant Proteins
Partnered Projects
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Global R&D Pipeline

December 08

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CSL718 Humate ® P
SCIg 20%
Zemaira ® US
Privigen®
IVIG 10%
GARDASIL®
Berinert ® Rhophylac ® ITP
Fibrinogen
US
New Indications
Zemaira® EU Beriplex ® EU
Beriplex®
Fibrinogen
New Indications Beriplex ® US
Congen Deficiency Afluria ® US
Fluvax ® China Afluria/Enzira® EU
CSL689
Rec coag factors Rec coag factorsrFVIIa-FP Vaccines– Merck
CSL654
Novel plasma rFIX-FP
proteins * Partnered Vaccine
Vaccines– Merck
Programs
Vaccines– Merck
Vaccines– Wyeth
CSL412
Vaccines – Wyeth CSL444 ISCOMATRIX® Flu
Beta common Pandemic
(Bion1/2) ISCOMATRIX® Flu
CAM3001 CSL401 CSL401
G-CSF CSL111 GM-CSFR - Pandemic FluPandemic Flu
reconstituted HDL CAT/AZ
Discovery projects
IL-13R Merck
CSL360 for AML
Core Capabilities Replacement Therapies Vaccines ISCOMATRIX® Adjuvant Therapeutic Proteins
Partnered Projects
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R&D Investment

Growth in new product and market development

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$Am
FY2009
~$270m
250
$225
200 $191 New Product Development
$161
150
Market development
100
Life Cycle Management
50
0
FY2006 FY2007 FY2008
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Building the R&D Pipeline

• Opportunities in current economic environment

• Process: high quality ideas in focus areas, efficient evaluation

• Integrated process across CSL Group to leverage full potential of networks

Sourcing, Detailed initial Review screening screening

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Due Diligence Negotiation
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In-license
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9

R&D Infrastructure and Facilities

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Bio21
Marburg
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Parkville
Celltrion / CMO
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GARDASIL®

Continued Growth Through Merck Life Cycle Management

• 2008: New indications and long-term evaluation

• Approved new indication for prevention of vulvar and vaginal cancer

• Ph 2 extension data with no breakthroughs through 5 years added to label

• 2008: new indications submitted for FDA review

• Efficacy in adult women to 45 years

• Efficacy in males

  • On target for submission to FDA in December 2008

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• R&D - V503: 9-Valent HPV Vaccine

• 5 additional HPV types

• Cover 87% cervical cancer

• Ph 3 trial underway

• Anticipate filing BLA in 2012

  • http://www.merck.com/newsroom/webcast/

Influenza Vaccine Program

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Global Influenza Vaccine Program

• Competitive advantages

• Expand influenza business

• Licensure obtained in Germany and Ireland in 2008

• Seeking additional registrations in Europe

• Regulatory dossier submitted to China SFDA

• US product launched October 07

  • Post-marketing clinical commitments

• Continued analysis of data and commercial opportunity for improved flu vaccine for elderly

Pandemic Vaccine Development

• Panvax® (avian influenza vaccine) approved June 2008 by Australian TGA

• Approval of paediatric indication expected Q2 2009

• Core Pandemic Dossier approved November 2008 by Singaporean HSA

• Adult, elderly and paediatric indications approved

Protein Replacement Therapies

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Profitable Litre Objective for Margin Expansion

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New markets
Wound
Healing New indications
Beriplex [®] P
Fibrin-
ogen Specialty Berinert [®] P
products Zemaira
FIX Haemocomplettan [®] P
Beriplex
API
Inhibitors Privigen [®]
SCIG
Factor VIIIs Rhophylac
Cytogam
Humate P
Immunoglobulins
Albumin
Litres PEQ
Margin growth
Revenue per litre
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Privigen[®]

• Only Room Temperature Stable IVIG

• Approved in key markets

• Licensed by FDA – July 2007

• Licensed by Health Canada - Jan 2008

• EMEA approval – April 2008

• Licensed by SwissMedic - April 2008

• New Manufacturing Facility

• SwissMedic Filed – October 2008

• FDA Filed – October 2008

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• Additional capacity in construction

IgPro20 – 20% Immunoglobulin for SC Treatment

• Minimal Dosage Volume for patient tolerance and convenience

• US trial is complete

• Submit US BLA mid-2009

• Currently running 3 Phase III trials

• Extension of US Pivotal Phase III

• European Phase III – Enrolment is complete

• Extension of European Phase III

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Specialty Products – Market Expansion

Beriplex[®] P/N – Market expansion

• PCC indicated for acute coagulation reversal

• Expansion into 16 new EU markets

• MRP completed in Jan 08

• Launch in UK (Mar 08), SE (May 08), NL (Sept 08), ES (Oct 08)

• Expansion into US market

• Clinical studies initiated in the US

• Production capacity enhancement

• Utilize plasma from other manufacturing sites

• Stable and transportable intermediate identified

• Evaluate potential new clinical indications

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Specialty Products – Market Expansion

Berinert[®] P

• C1 esterase inhibitor indicated for treatment of acute attacks of hereditary angioedema (Germany)

• Seek additional licenses in EU

• MRP procedure started in Sept 08

• Completion anticipated in Dec 08

• Canada

• BLA submitted April 08

• US

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• BLA submission in Mar 08

• Pre-approval inspection in May 08

• FDA response received

Specialty Products – Market Expansion

Haemocomplettan® P/(Fibrinogen)

• Indicated for congenital fibrinogen deficiency

• Market expansion in Europe and USA

• BLA submission July 08

• Phase III/IV efficacy study initiated Oct 08

• BPAC hearing in Jan 09

• EU submission Feb 09

• Production capacity enhancement

• Batch size & Freeze dry capacity increase

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• Evaluate potential new clinical indications

Progress in the Last Year on Other Projects

• Zemaira[®]

• Met enrollment target for Ph III/IV study

• Cytogam[®]

• Assure market supply

• Rhophylac[®]

• US approval of ITP study

• Vivaglobin[®]

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• Completed R&D activities

• Humate P[®]

• Completed R&D activities

Recombinant Coagulation Factors with extended half-life

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Half-life Improvement for Coagulation Products

Products with improved half-life will be beneficial to patients

• Less frequent injections

• Improved compliance

• May enable prophylaxis

Several technologies to extend half-life of proteins

• Sustained delivery

• Chemical modification

• Genetic mutation

• Fusion with carrier proteins (Fc fusion, Albumin)

Albumin as a Carrier Protein

• Albumin has a naturally long half-life (~20 days)

• Highly abundant protein

• Molecular structure is known

• Proof of principle data for FVIIa and FIX

Coagulation factor Albumin + short half-life long half-life

Albumin fusion Albumin = half-life extension

Half-life Extension of FVIIa and FIX

• FVIIa – indicated for treatment of inhibitor patients

• Half-life ~2.4 h

• Several infusions required for treatment:

  • 2

  • Joint bleeding:

  • Surgery: every 2 – 3 h for 2days

• => Goal for half-life extension: One infusion per bleeding event

• FIX – indicated for treatment of Hemophilia B

• Half-life ~20 h

• ~ 3 infusions required per week

• => Goal for half-life extension: One infusion per week

rFVIIa/ FIX - Albumin Fusion Proteins – Current status

• Preclinical target validation completed

• Significant Half-life extension in various animal models

  • rFVIIa: 5 to 9-fold

  • rFIX: 2 to 4-fold

• Comparable biological activity

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Pharmacokinetics / Rabbit
PSK 02/08
FVII
100
NovoSeven (MV Rabbit 1-3)
rFVIIa-FP CHO (MV Rabbit 1-3)
10
1
0 10 20 30 40 50 60 70 80
Time [hours]
% of initial dose
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  - In vitro

  - In vivo

• Construct for development defined

• Exclusive license from Novozymes

rFVIIa/ FIX – Albumin Fusion Proteins – Next Steps

• Using R&D capabilities across CSL Group

• Cell line development

• Process development

• Analytical method development

• Pharma/Tox program

• Clinical studies

• Regulatory submission

• GMP Material production

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Bio- Biother
CSL Behring Limited
plasma apies
Organization by site
MBG Bern K3 KoP Japan BMW PKV PKV
Integration via project management process
Organization by function
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Q&A

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Break

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ISCOMATRIX[®] Adjuvant Technology

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ISCOMATRIX[®] Adjuvant

• Proprietary biological adjuvant for use in humans

• Complex of ISCOPREP[®] saponin, cholesterol and phospholipid

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Integrated Mechanism of Action of ISCOMATRIX[®] Adjuvant

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Manufacture of ISCOPREP[®] Saponin and ISCOMATRIX[®] Adjuvant at Industrial Scale

• Developed pilot processes at Parkville

• Transferred to Kankakee, USA

• Scale-up at Kankakee

• ISCOPREP[®] saponin

• ISCOMATRIX[®] adjuvant

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Adjuvant
manufacturing
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Merck & Co. Inc. Recruiting Alzheimer’s Disease Vaccine Study

• Beta-amyloid vaccine formulated in aluminium with or without ISCOMATRIX® adjuvant

• Phase I study in patients with Alzheimer’s Disease

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AD monkey study
30000
20000
alum
10000 + IMX
0
Dose 1 Dose 2
beta GMT
anti-amyloid
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• Broad agreements in infectious diseases

• Evaluations continuing

Therapeutic Protein Portfolio Pre-clinical / early clinical projects

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rHDL: Potential Long Term Value

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JAMA -EXPRESS Effects of Reconstituted High-Density Lipoprotein Infusions on Coronary Atherosclerosis A Randomized Controlled Trial Jean-Claude Tardif, MD; Jean Grégoire, MD; Philippe L. L’Allier, MD; Reda Ibrahim, MD; Jacques Lespérance, MD; Therese M. Heinonen, DVM; Simon Kouz, MD; Colin Berry, MD; Russell Basser, MD; Marc-André - - Lavoie, MD; Marie Claude Guertin, PhD; Josep Rodés - Cabau, MD; for the Effect of rHDL on Atherosclerosis Safety and Efficacy (ERASE) Investigators

JAMA. 2007; 297:1675-1682.

Therapeutic Proteins

• CSL research at the Bio21 Institute

• capabilities, focus

• Project updates

Preclinical / early clinical projects

• CSL360, anti-IL-3Rα, acute myeloid leukemia

• anti-GM-CSFRα, rheumatoid arthritis

• G-CSF antagonists, inflammatory disease

• anti-IL-13Rα antagonists, asthma

Research projects

• IL-11 antagonists

• EphA4

• VEGF-B antagonists

• β common antagonists

Therapeutic Proteins

CSL Research at the Bio21 Institute

• research activity consolidated within a state-ofthe-art facility located in the heart of Australia’s premier medical research precinct

• focus on cytokines and cytokine receptors

• 65 staff with research groups specializing in Cell Biology/ Physiology, Molecular Biology and Protein Biochemistry

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• “in-house” and Bio21-based platform technologies

• leverage research activities through collaboration with leading academic groups

Therapeutic Proteins

CSL Research at the Bio21 Institute

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Academic Industry
focus focus
Collaborative interface
GMP manufacture
Target Target Drug Preclinical Clinical
Market
discovery validation discovery toxicology PhI + II + III
CSL Research activity
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α CSL360 (IL-3R ) - AML

CSL360 for acute myeloid leukemia

• Acute myeloid leukemia

• cancer of immature blood cells

• no major changes in treatment for last 20 years

• outcome depends on number of factors

< 50yrs old: 5yr survival 30-40%

• 60yrs old: 1yr survival 10-20%

• CSL360 Phase I clinical trial

• Phase I study in patients with relapsed, refractory or high-risk AML

• dose-escalation study (5 dose levels 0.1mg/kg -10mg/kg)

• multi-dose at weekly intervals (at least 4)

• study is continuing with 20 evaluable patients to be accrued and treated at 10mg/kg weekly

G-CSF Antagonists – Inflammatory Disease

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G-CSF
Neutrophils and inflammation X
Bone marrow
G-CSF
X
Blood
Site of infection/inflammation
From: Eyles et al Nat Clin Prac Rheum 2006
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G-CSF Antagonists – Inflammatory Disease

Does blockade of G-CSF impact on inflammation?

• G-CSF blockade in a mouse model of rheumatoid arthritis

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G-CSF gene KO mice are resistant Anti-G-CSF mAb inhibits
to the development of arthritis progression of arthritis
Lawlor et al .,
PNAS 101:11399,
2004
Day post disease induction Day of arthritis
Clinical severity Clinical severity
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Current R&D activities

• lead antibody selection and optimisation in progress

• Phase I clinical studies currently being planned

Partnered Projects

• anti-GM-CSFR α , rheumatoid arthritis

• licensed to MedImmune / AstraZeneca

• CAM3001 Phase I study in RA patients is ongoing - Phase Ib safety, tolerability and efficacy with s.c administration to commence Q1 2009

• anti-IL-13R α , asthma

• licensed to Merck & Co., Inc

• lead selection and characterisation in progress

Therapeutic Protein Portfolio Earlier Stage Research Projects

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IL-11 Antagonists – Cancer and Airway Disease

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Airways
Control inflammation
IL-11 antagonists
Airways
inflammation
Pegylated IL-11
mutein From: Lee et al ., Am J Respir Cell Mol Biol. 39:739, 2008
•
Collaborators
Gastric
- Yale University
cancer - Ludwig Institute for Cancer Research
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EphA4 Antagonists – Spinal Cord Injury

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Grasp test


4 WT
EphA4 antagonists
KO
After spinal cord injury EphA4 knockout
Improved motor 3
mice demonstrate:
function
- reduced glial scarring,
2
- increased nerve regeneration
- improved motor function 1
•
Collaborators
0
- The University of Melbourne
Axonal cont 1d 1m 2m 3m
- The University of Queensland
regeneration - QIMR time after spinal lesion
- WEHI
caudal Lesion site rostral
From: Goldshmit et al ., J. Neuroscience 24: 1064, 2004
Grasp score (units)
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VEGF-B Antagonists – Cancer and Eye Disease

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DU4475 Xenografts Treated with
VEGF-B antagonists anti-VEGF-B and Avastin
Breast carcinoma 1250
PBS
VEGF-B antagonists inhibit:
xenograft anti-VEGF-B
1000
- growth of breast carcinomas Avastin
750
- survival of new vessels in the eye
500
250
•
Collaborators
Blood vessel 0
- National Eye Inst., NIH (Xuri Li) 0 4 8 12 16 20 24 28 32
growth & Post Inoculation (Days)
- Ludwig Inst. For Cancer Research
survival
Unpublished, presented with kind permission of Dr. Xuri Li, National Eye Institute, Bethesda USA
Tumour Volume (mm3)
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β -Common Antagonists – Cancer and Inflammation

β -common – a shared receptor used by the cytokines IL-3, IL-5 and GM-CSF

GM-CSF – neutrophils, macrophages – RA, AML, CML IL-5 – eosinophils – asthma, atopic disease IL-3 – basophils, LSC & blasts - AML, asthma

• Collaborators

• IMVS, Adelaide - St Vincent's Research Institute

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GMR α
GM
β c
β c
Dodecamer
GM Complex
GMR α
site 4 specific antagonists
From: Hansen et al ., Cell 134: 496, 2008
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Global R&D Pipeline

December 08

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CSL718 Humate ® P
SCIg 20%
Zemaira ® US
Privigen®
IVIG 10%
GARDASIL®
Berinert ® Rhophylac ® ITP
Fibrinogen
US
New Indications
Zemaira® EU Beriplex ® EU
Beriplex®
Fibrinogen
New Indications Beriplex ® US
Congen Deficiency Afluria ® US
Fluvax ® China Afluria/Enzira® EU
CSL689
Rec coag factors rFVIIa-FP Vaccines– Merck
CSL654
Novel plasma rFIX-FP
proteins * Partnered Vaccine
Vaccines– Merck
Programs
Vaccines– Merck
Vaccines– Wyeth
CSL412
Vaccines – Wyeth CSL444 ISCOMATRIX® Flu
Beta common Pandemic
(Bion1/2) ISCOMATRIX® Flu
CAM3001 CSL401 CSL401
G-CSF CSL111 GM-CSFR - Pandemic Flu Pandemic Flu
reconstituted HDL CAT/AZ
Discovery projects
IL-13R Merck
CSL360 for AML
Core Capabilities Replacement Therapies Vaccines ISCOMATRIX® Adjuvant Therapeutic Proteins
Partnered Projects
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R&D Investment Strategy

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Continue to be fundamental to CSL’s ongoing success

Support the core business and develop bio-therapeutic products for our global commercial organization NPD increasing contribution to growth Committed to investing in future portfolio and capabilities

Q&A

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