Monoclonal antibody therapeutics 3/27/2017 Monoclonal antibody therapeutics SLA Pharmaceutical & Health Tech. Division April 2008 Janice Reichert, Ph.D. Senior Research Fellow Tufts CSDD, Tufts University

Topics Brief overview of industry and benchmarking Monoclonal antibody therapeutics Structure and function Global commercial development since 1980 Therapeutic categories Anti-cancer mAbs Immunological mAbs Anti-infective mAbs Future trends

Challenges facing the industry Competitive 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

Benchmark metrics Objective is to compare performance against a relative or absolute standard Important to compare ‘like’ therapeutics Allows assessment of efficiency and cost-effectiveness Important for strategic planning Tufts CSDD focus is on clinical development and approval

Input data IND filing date First administration to humans date Phase start dates (Phase 1, 2, 3) NDA or BLA submission date FDA approval date Status at discontinuation (Phase 1, 2, 3)

What can be calculated? Clinical development time Phase 1, 2, 3 times Approval time Clinical phase transition probabilities Approval success rates

Important categories Composition of matter Therapeutic category Small molecule Biopharmaceutical (rDNA, mAb, etc.) Therapeutic category FDA designations Orphan Priority or standard review Accelerated approval Fast track

Global focus on mAb therapeutics Acquisitions by major pharmaceutical firms Merck acquisition of Abmaxis, GlycoFi GSK acquisition of Domantis Eisai acquisition of Morphotek AstraZeneca acquisition of CAT, MedImmune Development in Asia First marketing approvals in China “Generic” mAbs in India and S. Korea

>US$ 1billion global markets* Remicade $4.4 billion Rituxan $3.9 billion Herceptin $3.1 billion Avastin $2.4 billion Humira $2.0 billion Erbitux $1.1 billion Synagis $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 proteins New technology addressing issues Immunogenicity Stability Affinity Specificity Production

Antibodies Five classes based on type of heavy chain IgA IgD IgE IgG – derived from B-cells, most abundant Ig IgM IgG has two primary functions Bind foreign antigens Eliminate or inactivate antigen

Structural features of IgG IgG are Y-shaped molecules Composed of a total of 4 protein chains 2 heavy chains with 1 variable and 3 constant domains 2 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 target Sequester soluble targets Target toxin or radiolabel to specific location Block targeted receptor Induce apoptosis Antibody dependent cell cytotoxicity (Fc dependent) Complement dependent cytotoxicity (Fc dependent) Sequester soluble targets Ligand binding

New mAb therapeutics, 1980-2007 World-wide clinical development of protein therapeutics by commercial sponsors Total > 500 candidates >200 in clinical studies Number approved 21 approved in US and other countries 3 approved outside US

Monoclonal Abs entering clinical study

Therapeutic proteins entering clinical study per year

Mab sequence source over time

Success rates for humanized mAbs US approval success rate = 17% (three in review) % completion = 49% Humanized mAbs, 1988-1997 N = 46 US approval success rate = 27% % completion = 80%

Therapeutic categories under study

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 date 9 approved in US 3 additional oncology mAbs approved in China

Oncology mAbs: first US approvals Rituxan 1997 Non-Hodgkin’s lymphoma Herceptin 1998 Breast cancer Mylotarg 2000 Acute myeloid leukemia Campath 2001 CLL Zevalin 2002 NHL Bexxar 2003 NHL Erbitux 2004 Colorectal cancer Avastin 2004 Colorectal cancer Vectibix 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 date 9 approved in US 3 in FDA review

Immuno. mAbs: 1st US approvals Orthoclone 1986 Transplant rejection Zenapax 1997 Transplant rejection Simulect 1998 Transplant rejection Remicade 1998 Crohn’s disease Humira 2002 Rheumatoid arthritis Xolair 2003 Allergy-related asthma Raptiva 2003 Psoriasis Tysabri 2004 Multiple sclerosis Soliris 2007 Paroxysmal nocturnal hemoglobinuria

Anti-infective mAb therapeutics 50 as of March 2008 18 (36%) currently in clinical development Number of anti-infective mAb approvals to date 1 approved in US 1 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 disease Tocilizumab In review (11/07), rheumatoid arthritis Ustekinumab In review (12/07), psoriasis Motavizumab In review (01/08), prevention of respiratory syncytial virus infection

Human mAb therapeutics Humira and Vectibix are human mAbs Fewer issues associated with immunogenicity Multiple methods for candidate selection Transgenic mouse Phage display Commercial production from CHO cells

Next generation mAbs Fragments, e.g. Fab, single chains Smaller, easier/less costly to manufacture But, shorter circulating half-life, no effector functions Approved Fabs: Reopro (1994) and Lucentis (2006) Modified versions Enhance ADCC/CDC functions Modify pharmacokinetic properties – pegylation Modify affinity and specificity – glycosylation, Fc region engineering

Future trends Opportunities in major therapeutic categories Anticancer therapeutics Immunological agents Anti-infective agents Increase in marketing approvals if success rates are consistent with previous rates Human mAbs Designed protein scaffolds/domains

Attraction 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 Fellow Tufts Center for the Study of Drug Development (617) 636-2182 janice.reichert@tufts.edu http://csdd.tufts.edu