Monoclonal antibody therapeutics

SLA Pharmaceutical & Health Tech. DivisionApril 2008

Janice Reichert, Ph.D.Senior Research FellowTufts CSDD, Tufts University

TopicsBrief overview of industry and benchmarkingMonoclonal antibody therapeutics

Structure and functionGlobal commercial development since 1980Therapeutic categories

Anti-cancer mAbsImmunological mAbsAnti-infective mAbs

Future trends

Challenges facing the industryChallenges facing the industryCompetitive markets

Industry globalization

Mergers, acquisitions, strategic alliances

Scientific and technological advances

Dynamic regulatory environment

High R&D costs

Long clinical development and approval times

Low approval success rates

Number of new US approvals/year

05

101520253035404550

1990

1992

1994

1996

1998

2000

2002

2004

2006

SMDs rDNA/mAbs

Benchmark metrics

Objective is to compare performance against a relative or absolute standard

Important to compare ‘like’ therapeuticsAllows assessment of efficiency and cost-

effectivenessImportant for strategic planningTufts CSDD focus is on clinical development

and approval

Input data

IND filing dateFirst administration to humans datePhase start dates (Phase 1, 2, 3) NDA or BLA submission dateFDA approval dateStatus at discontinuation (Phase 1, 2, 3)

What can be calculated?

Clinical development timePhase 1, 2, 3 timesApproval timeClinical phase transition probabilitiesApproval success rates

Important categories

Composition of matterSmall moleculeBiopharmaceutical (rDNA, mAb, etc.)

Therapeutic categoryFDA designations

OrphanPriority or standard reviewAccelerated approvalFast track

Global focus on mAb therapeutics

Acquisitions by major pharmaceutical firmsMerck acquisition of Abmaxis, GlycoFiGSK acquisition of DomantisEisai acquisition of MorphotekAstraZeneca acquisition of CAT, MedImmune

Development in AsiaFirst marketing approvals in China “Generic” mAbs in India and S. Korea

>US$ 1billion global markets*

Remicade $4.4 billionRituxan $3.9 billionHerceptin $3.1 billionAvastin $2.4 billionHumira $2.0 billionErbitux $1.1 billionSynagis $1.1 billion

*2006 sales, as reported in Med Ad News, July 2007

MAb therapeutics come of age

Established pathways to demonstrate safety, efficacy and quality

Innovative design of proteinsNew technology addressing issues

ImmunogenicityStabilityAffinitySpecificityProduction

AntibodiesFive classes based on type of heavy chain

IgAIgDIgEIgG – derived from B-cells, most abundant IgIgM

IgG has two primary functionsBind foreign antigensEliminate or inactivate antigen

Structural features of IgG

IgG are Y-shaped molecules

Composed of a total of 4 protein chains2 heavy chains with 1 variable and 3 constant domains2 light chains with 1 variable and 1 constant domain

Stem (Fc) of Y = 2x2 heavy chain constant domains

Each arm (Fab) of Y = 1 variable and 1 constant domain from heavy chain and 1 entire light chain.

Antibody structure

Functions of IgG

Cell-based targetTarget toxin or radiolabel to specific locationBlock targeted receptorInduce apoptosisAntibody dependent cell cytotoxicity (Fc dependent)Complement dependent cytotoxicity (Fc dependent)

Sequester soluble targetsLigand binding

New mAb therapeutics, 1980-2007

World-wide clinical development of protein therapeutics by commercial sponsors Total > 500 candidates >200 in clinical studies

Number approved21 approved in US and other countries 3 approved outside US

Monoclonal Abs entering clinical study

0

5

10

15

20

25

30

35

40

1980-84 1985-89 1990-94 1995-99 2000-04 2005-07

Ave. # of mAbs

Therapeutic proteins entering clinical study per year

0

5

10

15

20

25

30

35

40

1990-94 1995-99 2000-04 2005-2007

rDNAmAb

Mab sequence source over time

0

10

20

30

40

50

60

70

1980-89 1990-99 2000-05

MurineChimericHumanizedHuman

Success rates for humanized mAbsHumanized mAbs, 1988-2006

N = 131US approval success rate = 17% (three in review)% completion = 49%

Humanized mAbs, 1988-1997N = 46US approval success rate = 27%% completion = 80%

Therapeutic categories under study

0

10

20

30

40

50

60

70

80

90

1980-89 1990-99 2000-05

OncologyImmunol.Anti-infec.

Oncology mAb therapeutics

Number of oncology mAb therapeutics>270 as of March 2008 121 (44%) currently in clinical development

Number of oncology mAb approvals to date9 approved in US3 additional oncology mAbs approved in China

Oncology mAbs: first US approvalsRituxan 1997 Non-Hodgkin’s

lymphomaHerceptin 1998 Breast cancerMylotarg 2000 Acute myeloid leukemiaCampath 2001 CLLZevalin 2002 NHLBexxar 2003 NHLErbitux 2004 Colorectal cancerAvastin 2004 Colorectal cancerVectibix 2006 Colorectal cancer

Immunological mAb therapeutics

‘Immunological’ indications include rheumatoid arthritis, psoriasis, Crohn’s disease, allergy/asthma, transplant rejection, etc.

Immunological mAb therapeutics>120 as of March 2008 56 (46%) currently in clinical development

Number of immunological mAb approvals to date9 approved in US3 in FDA review

Immuno. mAbs: 1st US approvalsOrthoclone 1986 Transplant rejectionZenapax 1997 Transplant rejectionSimulect 1998 Transplant rejectionRemicade 1998 Crohn’s diseaseHumira 2002 Rheumatoid arthritisXolair 2003 Allergy-related asthmaRaptiva 2003 PsoriasisTysabri 2004 Multiple sclerosisSoliris 2007 Paroxysmal nocturnal

hemoglobinuria

Anti-infective mAb therapeutics

Anti-infective mAb therapeutics50 as of March 2008 18 (36%) currently in clinical development

Number of anti-infective mAb approvals to date1 approved in US1 in FDA review

Anti-infective mAb: 1st US approval

Synagis 1998 Prevention of respiratory syncytial virus infection

Four mAbs in FDA review

Certolizumab pegol In review (3/07), Crohn’s diseaseTocilizumab In review (11/07), rheumatoid

arthritisUstekinumab In review (12/07), psoriasisMotavizumab In review (01/08), prevention of

respiratory syncytial virus infection

Human mAb therapeutics

Humira and Vectibix are human mAbsFewer issues associated with immunogenicityMultiple methods for candidate selection

Transgenic mouse Phage display

Commercial production from CHO cells

Next generation mAbs

Fragments, e.g. Fab, single chainsSmaller, easier/less costly to manufactureBut, shorter circulating half-life, no effector functionsApproved Fabs: Reopro (1994) and Lucentis (2006)

Modified versionsEnhance ADCC/CDC functions Modify pharmacokinetic properties – pegylation Modify affinity and specificity – glycosylation, Fc region

engineering

Future trends

Opportunities in major therapeutic categoriesAnticancer therapeutics Immunological agentsAnti-infective agents

Increase in marketing approvals if success rates are consistent with previous rates

Human mAbsDesigned protein scaffolds/domains

Attraction of mAbsAttraction of mAbs

Expansion of therapeutics pipeline

High(er) approval success rates

Established development and approval pathways

Established production methods

Competitive research and development times

Potentially large markets

Questions? Comments?

Janice Reichert, Ph.D.Editor-in-Chief, MAbs (Landes Bioscience, launch in January 2009)http://www.landesbioscience.com/journals/mabs

Senior Research FellowTufts Center for the Study of Drug Development(617) 636-2182janice.reichert@tufts.eduhttp://csdd.tufts.edu