Biotechnology PRESENTED by AMERICA’ S PHARMACEUTICAL COMPANIES 324 Biotechnology Medicines in Testing Promise to Bolster the Arsenal Against Disease

2004Survey M EDICINES IN D EVELOPMENT Biotechnology PRESENTED BY AMERICA’ S PHARMACEUTICAL COMPANIES 324 Biotechnology Medicines in Testing Promise to Bolster the Arsenal Against Disease

illions of people have already benefited from B IOTECHNOLOGY M EDICINES IN D EVELOPMENT— medicines and vaccines developed through B Y T HERAPEUTIC C ATEGORY* Mbiotechnology, and a new survey offers hope that many more will benefit in the future. The survey AIDS/HIV Infection/Related Conditions 17 found 324 biotechnology medicines in development for Autoimmune Disorders 26 Blood Disorders 2 nearly 150 diseases. These include 154 medicines for Cancer/Related Conditions 154 cancer, 43 for infectious diseases, 26 for autoimmune dis- Cardiovascular Disease 19 eases and 17 for AIDS/HIV and related conditions. These Diabetes/Related Conditions 10 potential medicines, all of which are either in human Digestive Disorders 11 clinical trials or under review by the Food and Drug Eye Conditions 5 Genetic Disorders 9 Administration, will bolster the list of 108 biotechnology Growth Disorders 3 medicines already approved and available to patients. Infectious Diseases 43 Neurologic Disorders 16 Approved biotechnology medicines treat or help prevent Respiratory Disorders 14 heart attacks, stroke, multiple sclerosis, leukemia, hepatitis, Skin Disorders 7 rheumatoid arthritis, breast cancer, diabetes, congestive Transplantation 3 heart failure, lymphoma, kidney cancer, cystic fibrosis, Other 17 and other diseases. These medicines are based on several *Some medicines are listed in more than one category. cutting-edge technologies. For example, most early biotechnology medicines were protein drugs, produced an epidermal growth factor inhibitor, which targets and by splicing genes into bacteria. They include recombi- blocks signaling pathways that are implicated in the growth nant insulin, human growth hormone, clotting factor for and survival of cancer cells. Monoclonal antibody medicines hemophilia patients, and erythropoietin to stimulate the in the pipeline target asthma, Crohn’s disease, rheumatoid production of red blood cells in kidney dialysis and arthritis, lupus, and various types of cancer. Therapeutic cancer patients. Another type of biotechnology medicine, vaccines, designed to jump-start the immune system to the monoclonal antibody, is a laboratory-made version of fight disease, are in development for AIDS and several the naturally occurring protein that binds to and neutral- types of cancer. Medicines based on antisense technol- izes foreign invaders. The first recombinant monoclonal ogy are potential treatments for AIDS, several types of antibody that inhibits angiogenesis—the formation of new cancer, Crohn’s disease and heart disease. Gene thera- blood vessels that feed tumors—was approved this year pies, which augment normal gene functions or replace for the treatment of metastatic colorectal cancer. or inactivate disease-causing genes, are being tested for Interferons, proteins that interfere with the ability of a cell several cancers, cystic fibrosis and heart disease. to reproduce, are the basis of existing medicines for These are only a few examples of new ways pharma- osteoporosis, chronic granulomatous disease, genital ceutical and biotechnology companies are attacking warts, multiple sclerosis, hairy cell leukemia and other disease. The 324 biotechnology medicines in develop- diseases. Antisense drugs are medicines that interfere ment promise to push the frontiers of science and bring with the communication process that tells a cell to more and better treatments to patients. produce an unwanted protein. The first antisense drug, for the treatment of cytomegalovirus retinitis in AIDS patients, was approved in 1998. The biotechnology medicines in development make Alan F. Holmer use of these and other state-of-the-art technologies. For President and CEO example, one medicine in the pipeline for lung cancer is PhRMA Biotechnology Medicines in Development AIDS/HIV INFECTION AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Alferon LDO® Hemispherx Biopharma interferon HIV infection Phase I/II New Brunswick, NJ (888) 253-3766 Philadelphia, PA ALVAC E120TMG Aventis Pasteur vaccine HIV infection Phase III Swiftwater, PA (Thailand) (570) 839-4267 ALVAC MN120 Aventis Pasteur therapeutic HIV disease Phase I/II TMGMP Swiftwater, PA vaccine (570) 839-4267 Ampligen® Hemispherx Biopharma immune HIV infection/AIDS Phase II New Brunswick, NJ modulator (see also autoimmune) (215) 988-0080 Philadelphia, PA AVR 118 Advanced Viral Research immune-based cachexia associated with Phase I/II Yonkers, NY therapy AIDS (914) 376-7383 (see also cancer) Doxovir™ Redox Pharmaceutical HIV infection Phase I New York, NY (see also infectious) (212) 543-4530 GEM® 92 Hybridon antisense HIV infection Phase I completed Cambridge, MA (617) 679-5500 HE2000 Hollis-Eden Pharmaceuticals cellular therapy HIV infection/AIDS Phase I/II completed San Diego, CA (see also genetic, (858) 587-9333 infectious) HIV vaccine Chiron vaccine HIV infection Phase I Emeryville, CA www.hvtn.com National Institutes of Health Bethesda, MD HIV vaccine GlaxoSmithKline recombinant HIV infection prophylaxis Phase I Philadelphia, PA vaccine (888) 325-5249 Rsch. Triangle Park, NC HIV vaccine Merck vaccine treatment and prevention Phase I Whitehouse Station, NJ of HIV infection/AIDS (800) 672-6372 IL-2 Bayer interleukin HIV infection Phase I West Haven, CT (see also cancer) (203) 812-2000 MDX-010 Medarex MAb HIV infection Phase I/II Princeton, NJ (see also cancer) (609) 430-2880 Prosaptide™ Savient Pharmaceuticals neurostimulatory HIV-associated Phase II prosaptide East Brunswick, NJ peptide neuropathic pain (800) 284-2480 Remune® Immune Response immune-based HIV seropositive Phase II HIV-1 immunogen Carlsbad, CA therapy (760) 431-7080 Serostim® Serono recombinant HIV-related adipose Phase III somatropin Rockland, MA growth redistribution syndrome (800) 283-8088 (rDNA origin) hormone for injection

2 M EDICINES IN D EVELOPMENT Biotechnology 2004 AIDS/HIV INFECTION AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status VRC-HIVADV GenVec vaccine HIV infection Phase I 014-00-VP Gaithersburg, MD (240) 632-0740 Vaccine Research Center/ NIAID/NIH Bethesda, MD

A UTOIMMUNE D ISORDERS Product Product Development Name Sponsor Category Indication Status ABT-874 Abbott Laboratories MAb autoimmune disease Phase II Abbott Park, IL (847) 936-1189 AMG108 Amgen MAb arthritis Phase II Thousand Oaks, CA (805) 447-1000 AMG531 Amgen platelet immune thrombocytopenic Phase II Thousand Oaks, CA stimulating purpura (ITP) (805) 447-1000 factor AMG714 Amgen MAb rheumatoid arthritis Phase II Thousand Oaks, CA (805) 447-1000 Ampligen® Hemispherx Biopharma immune chronic fatigue syndrome Phase III New Brunswick, NJ modulator (see also AIDS/HIV) (215) 988-0080 Philadelphia, PA anti-CD20 Immunomedics MAb autoimmune disease Phase I humanized Morris Plains, NJ (see also cancer) (973) 605-8200 anti-clonal antibody anti-TGF beta Genzyme MAb diffuse scleroderma Phase II (Orphan Drug) Cambridge, MA (800) 745-4447 Avonex® Biogen Idec interferon chronic inﬂammatory Phase II interferon beta-1a Cambridge, MA demyelinating (617) 679-2000 polyneuropathy (CIDP) CDP 870 Nektar Therapeutics pegylated rheumatoid arthritis Phase III San Carlos, CA antibody (650) 631-3100 fragment eculizumab Alexion Pharmaceuticals MAb lupus nephritis, Phase II (Orphan Drug) Cheshire, CT membranous nephritis, (203) 272-2596 rheumatoid arthritis (see also skin) humanized Genentech MAb rheumatoid arthritis Phase I/II anti-CD20 South San Francisco, CA (650) 225-1000 (PRO70769) Humira Abbott Laboratories MAb ankylosing spondylitis, Phase III adalimumab Abbott Park, IL juvenile rheumatoid (847) 936-1189 arthritis, psoriatic arthritis (see also digestive, skin) interferon InterMune interferon idiopathic pulmonary Phase III gamma Brisbane, CA ﬁbrosis (415) 466-2200 (see also cancer)

M EDICINES IN D EVELOPMENT Biotechnology 2004 3 A UTOIMMUNE D ISORDERS Product Product Development Name Sponsor Category Indication Status interleukin-1 Regeneron Pharmaceuticals interleukin rheumatoid arthritis Phase II trap Tarrytown, NY (914) 345-7400 ISIS 104838 Isis Pharmaceuticals antisense rheumatoid arthritis Phase II Carlsbad, CA (800) 679-ISIS LymphoStat-B™ Human Genome Sciences MAb rheumatoid arthritis, Phase II Rockville, MD systemic lupus www.hgsi.com erythematosus MDX-018 Medarex MAb autoimmune disease Phase I/II Princeton, NJ (609) 430-2880 MLN 1202 Millennium MAb rheumatoid arthritis Phase II Pharmaceuticals (800) 589-9005 Cambridge, MA MM-093 Merrimack Pharmaceuticals recombinant rheumatoid arthritis Phase II (recombinant Cambridge, MA protein (617) 441-1000 human alpha-fetoprotein) R1569 MRA Roche MAb juvenile idiopathic Phase II (tocilizumab) Nutley, NJ arthritis, rheumatoid (973) 235-5000 arthritis Rituxan® Genentech MAb anti-TNF refractory Phase III rituximab South San Francisco, CA rheumatoid arthritis (650) 225-1000 Biogen Idec (see also cancer) Cambridge, MA ------primary progressive Phase II/III multiple sclerosis (650) 225-1000 ------moderate to severe Phase II rheumatoid arthritis (650) 225-1000 TACI-lg Serono recombinant lupus Phase II Rockland, MA protein (see also cancer) (800) 283-8088 ------rheumatoid Phase I arthritis (800) 283-8088 tadekinig-α Serono recombinant rheumatoid arthritis in clinical trials (IL-18bp) Rockland, MA protein (see also skin) (800) 283-8088 tgAAV94 Targeted Genetics gene therapy rheumatoid arthritis Phase I Seattle, WA (206) 623-7612 Veldona® Amarillo Biosciences interferon Sjogren’s syndrome Phase III natural human Amarillo, TX (806) 376-1741 interferon-alpha ------ﬁbromyalgia syndrome Phase II (806) 376-1741 Vitaxin MedImmune MAb rheumatoid arthritis Phase II anti-angiogenesis Gaithersburg, MD (see also cancer, skin) (301) 398-0000 MAb

4 M EDICINES IN D EVELOPMENT Biotechnology 2004 B LOOD D ISORDERS Product Product Development Name Sponsor Category Indication Status Dynepo® Aventis Pharmaceuticals gene-activated anemia associated with Phase III epoietin delta Bridgewater, NJ erythropoietin renal disease (973) 394-6000 Transkaryotic Therapies protein (617) 349-0200 Cambridge, MA ------anemia associated with Phase III cancer chemotherapy (973) 394-6000 (617) 349-0200 R744 CERA Roche renal anemia Phase III Nutley, NJ (973) 235-5000 ------cancer-related anemia Phase II (973) 235-5000

C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status γ-fowlpox-CEA (6D)/ National Cancer Institute vaccine CEA-expressing tumors Phase I/II tricom vaccine Bethesda, MD NCI TRIAL (800) 4-CANCER γ-fowlpox-GM-CSF National Cancer Institute vaccine CEA-expressing cancers Phase I vaccine Bethesda, MD NCI TRIAL (800) 4-CANCER γ-fowlpox PSA National Cancer Institute vaccine prostate cancer Phase II vaccine Bethesda, MD NCI TRIAL (800) 4-CANCER γ-fowlpox, National Cancer Institute vaccine head and neck cancer, Phase I r-vaccinia-tricom Bethesda, MD melanoma N C I T RIAL vaccine (800) 4-CANCER 249553 GlaxoSmithKline recombinant treatment of lung cancer, Phase II (mage 3) Philadelphia, PA vaccine melanoma (888) 825-5249 Rsch. Triangle Park, NC 251353 GlaxoSmithKline prevention of chemo- Phase I (Groβ-T Philadelphia, PA therapy-induced (888) 825-5249 CXC chemokine) Rsch. Triangle Park, NC cytopenias 485232 GlaxoSmithKline interleukin immunologically-sensitive Phase I (recombinant Philadelphia, PA cancers (melanoma, renal (888) 825-5249 human IL-18 Rsch. Triangle Park, NC cell) immunomodulator) adenovirus p53 National Cancer Institute gene therapy glioma, lung cancer Phase I/II Bethesda, MD NCI TRIAL Introgen Therapeutics (800) 4-CANCER Austin, TX

M EDICINES IN D EVELOPMENT Biotechnology 2004 5 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Advexin® Introgen Therapeutics gene therapy head and neck cancer Phase III Austin, TX (866) 631-4646 ------breast, lung cancers Phase II (866) 631-4646 ------bladder, brain, ovarian, Phase I prostate cancers (866) 631-4646 Afﬁnitak™ Isis Pharmaceuticals antisense non-small-cell lung cancer Phase III Carlsbad, CA (NSCLC) (800) 679-ISIS AFP-Scan® Immunomedics MAb, Fab´ location and extent of Phase II technetium-99m- Morris Plains, NJ fragment disease staging of liver (973) 605-8200 FAb´ fragment and germ cell cancers AHM Roche MAb multiple myeloma Phase I (anti-HM1.24 Nutley, NJ (973) 235-5000 MAb) Allovectin-7® Vical gene therapy advanced metastatic Phase II completed High Dose San Diego, CA melanoma (858) 646-1100 DNA/lipid complex encoding HLA-B7 antigen ALVAC-CEA/B7.1 Aventis Pasteur vaccine colorectal cancer Phase II Swiftwater, PA www. Aventis Pharmaceuticals cancervaccines.com Bridgewater, NJ ALVAC gp100 Aventis Pasteur vaccine melanoma Phase I/II Swiftwater, PA www. cancervaccines.com AMG114 Amgen erythropoietic chemotherapy-induced Phase I/II Thousand Oaks, CA protein anemia (805) 447-1000 AMG162 Amgen recombinant bone metastases Phase II Thousand Oaks, CA protein (see also other) (805) 447-1000 Angiocol™ BioStratum recombinant colorectal cancer, Phase I Durham, NC collagen melanoma (919) 433-1000 anti-CD20 Immunomedics MAb non-Hodgkin’s lymphoma Phase I/II humanized Morris Plains, NJ (see also autoimmune) (973) 605-8200 anti-clonal antibody anti-Tac(Fv)-PE38 National Cancer Institute MAb+toxin leukemia, lymphoma Phase I/II immunotoxin Bethesda, MD NCI TRIAL (800) 4-CANCER APC8024 Dendreon vaccine breast, colon, ovarian Phase I completed Seattle, WA cancers (206) 256-4545 Aptosyn® OSI Pharmaceuticals selective familial adenomatous Phase II exisulind Melville, NY apoptotic polyposis (FAP) (800) 572-1932 antineoplastic drug

6 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status autologous National Cancer Institute vaccine melanoma Phase II gp100-reactive Bethesda, MD NCI TRIAL PBL and TIL plus (800) 4-CANCER RF-gp100P209 Avastin™ Genentech MAb NSCLC, renal cell, breast, Phase III bevacizumab South San Francisco, CA pancreatic cancers (650) 225-1000 AVR 118 Advanced Viral Research immune-based cachexia associated with Phase I/II Yonkers, NY therapy leukemias, lymphomas, (914) 376-7383 solid tumors (see also AIDS/HIV) BCX-1777 BioCryst Pharmaceuticals purine T-cell-related leukemias Phase II Birmingham, AL nucleoside and lymphomas (205) 444-4600 phosphorylase inhibitor bevacizumab National Cancer Institute MAb several cancers Phase I/II/III Bethesda, MD NCI TRIAL Genentech (800) 4-CANCER South San Francisco, CA BIOVAXID™ Accentia cellular indolent follicular Phase III FNHLIdl Biopharmaceuticals therapy non-Hodgkin’s lymphoma (877) 654-6052 Morrisville, NC Biovest International Minneapolis, MN BrevaRex™ AltaRex MAb breast cancer, multiple Phase I completed antibody-based Waltham, MA myeloma, MUC1-expressing (781) 672-0138 immunotherapy tumors CA4P OXiGENE vascular anaplastic thyroid cancer Phase II Watertown, MA targeting agent (see also eye) (617) 673-7800 ------gastrointestinal, ovarian Phase I/II cancers, solid tumors (617) 673-7800 ------head and neck, lung, Phase I prostate cancers (617) 673-7800 CAL Roche MAb bone metastases Phase II Nutley, NJ (973) 235-5000 Campath® National Cancer Institute MAb leukemia, lymphoma Phase I/II alemtuzumab Bethesda, MD NCI TRIAL (800) 4-CANCER cantuzumab ImmunoGen MAb conjugate colorectal, gastric, NSCLC, Phase I/II mertansine Cambridge, MA pancreatic cancers (617) 995-2500 Canvaxin™ CancerVax immune-based stage III and stage IV Phase III (Orphan Drug) Carlsbad, CA therapy melanoma (760) 494-4200

M EDICINES IN D EVELOPMENT Biotechnology 2004 7 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status carcinoembryonic National Cancer Institute vaccine gastrointestinal tract Phase II antigen peptide-1 Bethesda, MD cancer N C I T RIAL vaccine (800) 4-CANCER CEA-Cide™ Immunomedics MAb breast, colorectal cancers Phase I humanized Morris Plains, NJ (973) 605-8200 anti-CEA antibody CEA-Cide Y-90™ Immunomedics MAb colorectal, pancreatic Phase II Morris Plains, NJ cancers (973) 605-8200 CEA-Scan™ Immunomedics MAb, Fab´ location and extent of Phase III technetium-99m- Morris Plains, NJ fragment disease staging of lung (973) 605-8200 arcitumomab cancer ------location and extent Phase II of disease staging (973) 605-8200 of breast cancer CEP-7055 Cephalon signaling, solid tumors Phase I West Chester, PA angiogenesis (610) 344-0200 inhibitor, VEGF receptor CG7870 Cell Genesys oncolytic virus prostate cancer Phase I/II South San Francisco, CA therapy (650) 266-3000 chimeric MAb National Cancer Institute MAb neuroblastoma Phase III 14.18 Bethesda, MD NCI TRIAL (800) 4-CANCER Cotara™ Peregrine Pharmaceuticals MAb malignant glioma Phase II/III 131-I-chTNT-I/B Tustin, CA (714) 508-6000 MAb ------(Orphan Drug) colorectal cancer, solid Phase I tumors (714) 508-6000 CP-547,632 OSI Pharmaceuticals VEGF solid tumors Phase II Melville, NY (800) 572-1932 Pﬁzer New York, NY D1/3-MAGE3 National Cancer Institute vaccine melanoma Phase II fusion protein Bethesda, MD NCI TRIAL vaccine (800) 4-CANCER epratuzumab Immunomedics humanized non-Hodgkin’s B-cell Phase III (unlabeled) Morris Plains, NJ MAb lymphoma (973) 605-8200 epratuzumab/Y90 Immunomedics humanized non-Hodgkin’s B-cell Phase I/II Morris Plains, NJ MAb lymphoma (973) 605-8200 Erbitux® Bristol-Myers Squibb MAb early-stage colorectal, Phase III cetuximab Princeton, NJ head and neck, NSCLC, (877) 925-6631 ImClone Systems pancreatic cancers New York, NY ESO-1:157-165 National Cancer Institute vaccine metastatic cancers Phase II (165V) peptide Bethesda, MD NCI TRIAL vaccine (800) 4-CANCER

8 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Ewing’s sarcoma National Cancer Institute vaccine sarcoma Phase II and alveolar Bethesda, MD NCI TRIAL rhabdomyosarcoma (800) 4-CANCER peptide vaccine FGF peptides National Cancer Institute peptide renal cancer Phase II Bethesda, MD NCI TRIAL (800) 4-CANCER GEM®231 Hybridon antisense solid tumors (monotherapy Phase II Cambridge, MA and in combination with (617) 679-5500 taxanes) Genasense® Aventis Pharmaceuticals antisense acute myelogenous Phase III oblimersen sodium Bridgewater, PA leukemia (AML), chronic (973) 394-6000 Genta lymphocytic leukemia Berkeley Heights, NJ (CLL), malignant melanoma, multiple myeloma GMK cancer Progenics vaccine prevention of recurrence Phase III vaccine Tarrytown, NY following surgery to (914) 789-2800 remove primary melanoma in high-risk patients GnRH pharmaccine Aphton vaccine reproductive system Phase II Miami, FL and prostate cancers www.aphton.com gp100 peptide National Cancer Institute vaccine melanoma Phase II/III vaccine Bethesda, MD NCI TRIAL (800) 4-CANCER gp100 protein National Cancer Institute vaccine melanoma Phase I/II (184V) Bethesda, MD NCI TRIAL (800) 4-CANCER GVAX® Leukemia Cell Genesys vaccine AML Phase II cancer vaccine South San Francisco, CA (650) 266-3000 GVAX® Lung Cell Genesys vaccine lung cancer Phase II cancer vaccine South San Francisco, CA (650) 266-3000 GVAX® Myeloma Cell Genesys vaccine multiple myeloma Phase I/II cancer vaccine South San Francisco, CA (650) 266-3000 GVAX® Pancreatic Cell Genesys vaccine pancreatic cancer Phase II cancer vaccine South San Francisco, CA (650) 266-3000 GVAX® Prostate Cell Genesys vaccine hormone refractory Phase III cancer vaccine South San Francisco, CA prostate cancer (650) 266-3000 HER-2 neu GlaxoSmithKline recombinant treatment of breast cancer Phase I recombinant Philadelphia, PA vaccine (888) 835-5249 therapeutic Rsch. Triangle Park, NC vaccine Her2/neu Corixa vaccine breast, ovarian cancers Phase I vaccine Seattle, WA (206) 366-3700 Herceptin® Genentech MAb adjuvant treatment in Phase III trastuzumab South San Francisco, CA early-stage HER2-positive (650) 225-1000 breast cancer

M EDICINES IN D EVELOPMENT Biotechnology 2004 9 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status HGS-ETR1 Human Genome Sciences MAb hematologic and Phase I Rockville, MD solid tumors www.hgsi.com HGS-ETR2 Human Genome Sciences MAb hematologic and Phase I Rockville, MD solid tumors www.hgsi.com HPV 16, E6 and E7 National Cancer Institute vaccine cervical cancer Phase I peptide vaccine Bethesda, MD NCI TRIAL (800) 4-CANCER HPV vaccine MedImmune vaccine cervical cancer Phase III Gaithersburg, MD (see also infectious) (301) 398-0000 GlaxoSmithKline (888) 825-5249 Philadelphia, PA Rsch. Triangle Park, NC HPV vaccine Merck vaccine prevention of cervical Phase III Whitehouse Station, NJ cancer and genital warts due to human papillomavirus (HPV) infection (see also infectious) huN901-DM1 ImmunoGen MAb conjugate multiple myeloma, other Phase I/II Cambridge, MA neuroendocrine cancers, (617) 995-2500 small-cell lung cancer (SCLC) IL-2 Bayer interleukin cancer treatment Phase II West Haven, CT (see also AIDS/HIV) (203) 812-2000 IL13-PE38QQR NeoPharm recombinant glioblastoma multiforme Phase III (Orphan Drug) Lake Forest, IL and other malignant (847) 295-8678 gliomas IMC-BEC2 ImClone Systems vaccine SCLC Phase III New York, NY (877) 925-6631 IMC-GP75 ImClone Systems vaccine melanoma Phase I New York, NY (877) 925-6631 immunotoxin BL22 National Cancer Institute immunotoxin leukemia, lymphoma Phase I/II Bethesda, MD NCI TRIAL (800) 4-CANCER INGN 241 Introgen Therapeutics gene therapy melanoma Phase II Austin, TX (866) 631-4646 ------solid tumors Phase I (866) 631-4646 Insegia™ Aphton vaccine advanced pancreatic Phase III anti-gastrin 17 Miami, FL cancer www.aphton.com (see also digestive) ------advanced stomach, Phase II completed esophageal cancers www.aphton.com interferon gamma InterMune interferon ovarian cancer Phase III Brisbane, CA (see also autoimmune) (415) 466-2200

10 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status interleukin-4 National Cancer Institute interleukin breast, colorectal, ovarian Phase I/II (IL-4) Bethesda, MD cancers, leukemia, N C I T RIAL Schering-Plough lymphoma, melanoma, (800) 4-CANCER Kenilworth, NJ sarcoma KOS-862 Kosan Biosciences cancer, including taxane- Phase II epothilone D Hayward, CA resistant tumors (510) 732-8400 LEP-ETU NeoPharm antisense advanced cancers, Phase I Lake Forest, IL including breast, lung and (847) 295-8678 ovarian LEP-SN38 NeoPharm pro-drug advanced cancers, Phase I/II Lake Forest, IL including colorectal and (847) 295-8678 lung LErafAON NeoPharm antisense advanced cancers, Phase I Lake Forest, IL including pancreatic (847) 295-8678 Lestaurtinib Cephalon signaling, acute myeloid leukemia Phase II CEP-701 West Chester, PA ﬂt-3 receptor (AML), prostate cancer (610) 344-0200 inhibitor LymphoRad™ 131 Human Genome Sciences radiodinated multiple myeloma Phase I Rockville, MD protein www.hgsi.com LymphoScan® Immunomedics MAb, Fab´ location and extent of Phase III technetium-99m- Morris Plains, NJ fragment disease staging of (973) 605-8200 bectumomab non-Hodgkin’s B-cell (lymphoma) lymphoma, detection of residual disease following radiation/chemotherapy M200 Protein Design Labs chimeric solid tumors Phase I Fremont, CA antibody (510) 574-1400 MAb HeFi-1 National Cancer Institute MAb lymphoma, non-Hodgkin’s Phase I Bethesda, MD lymphoma N C I T RIAL (800) 4-CANCER MAb Hu1D10 National Cancer Institute MAb leukemia, non-Hodgkin’s Phase I Bethesda, MD lymphoma N C I T RIAL Protein Design Labs (800) 4-CANCER Fremont, CA MAb MEDI-522 National Cancer Institute MAb advanced cancers Phase I Bethesda, MD NCI TRIAL MedImmune (800) 4-CANCER Gaithersburg, MD MART-1 National Cancer Institute vaccine metastatic melanoma Phase II melanoma Bethesda, MD NCI TRIAL vaccine (800) 4-CANCER MDX-010 Medarex MAb breast cancer, malignant Phase II Princeton, NJ melanoma, prostate (609) 430-2880 cancer (see also AIDS) MDX-010 +/- DTIC Medarex MAb melanoma Phase II Princeton, NJ (609) 430-2880

M EDICINES IN D EVELOPMENT Biotechnology 2004 11 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status MDX-010 + gp100 Medarex MAb melanoma Phase II peptides Princeton, NJ (609) 430-2880 MDX-060 Medarex MAb CD30+ lymphomas Phase I/II Princeton, NJ (Hodgkin’s disease, (609) 430-2880 anaplastic large cell lymphoma) MDX-070 Medarex MAb prostate cancer Phase II Princeton, NJ (609) 430-2880 MDX-1307 Medarex MAb colon cancer Phase I Princeton, NJ (609) 430-2880 MLN591 Millennium MAb prostate cancer Phase I Pharmaceuticals (800) 589-9005 Cambridge, MA BZL Biologics Framingham, MA MLN2704 Millennium MAb androgen-independent Phase I/II Pharmaceuticals prostate cancer (800) 589-9005 Cambridge, MA BZL Biologics Framingham, MA myeloma-derived National Cancer Institute vaccine multiple myeloma Phase I/II idiotypic antigen Bethesda, MD NCI TRIAL vaccine (800) 4-CANCER NBI-3001 Neurocrine Biosciences IL-4 fusion malignant glioma Phase II (IL-4 PE) San Diego, CA toxin (858) 658-7600 ------kidney, lung cancers Phase I (858) 658-7600 Norelin™ YM Biosciences recombinant prostate cancer Phase I/II recombinant GrNH Mississauga, Ontario protein (905) 629-9761 protein Omnitarg™ Genentech MAb HER2-negative breast, Phase II pertuzumab South San Francisco, CA NSCLC, ovarian, prostate (650) 225-1000 cancers Oncophage® Antigenics heat shock melanoma, renal cell Phase III HSPPC-96 New York, NY protein carcinoma (781) 674-4400 (Orphan Drug) Ontak® Ligand Pharmaceuticals fusion protein B-cell non-Hodgkin’s Phase II denileukin diftitox San Diego, CA lymphoma, CLL, PTCL (858) 550-7500 (see also skin) OSI-461 OSI Pharmaceuticals selective CLL, prostate, Phase I/II Melville, NY apoptotic renal cell cancers (800) 572-1932 antineoplastic (see also digestive) drug OvaRex™ AltaRex MAb ovarian cancer Phase III completed antibody-based Waltham, MA (781) 672-0138 immunotherapy

12 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status p53 and RAS National Cancer Institute vaccine breast, colon, ovarian Phase I/II vaccine Bethesda, MD cancers N C I T RIAl (800) 4-CANCER palifermin Amgen recombinant oral mucositis application Thousand Oaks, CA growth factor submitted (805) 447-1000 panitumumab Abgenix MAb colorectal cancer Phase II (ABX-EGF) Fremont, CA (510) 608-6500 Amgen (805) 447-1000 Thousand Oaks, CA PANVAC-V/F National Cancer Institute vaccine colon cancer, Phase I Bethesda, MD solid tumors N C I T RIAL (800) 4-CANCER PANVAC™-VF Therion Biologics vaccine metastatic pancreatic Phase III Cambridge, MA cancer (617) 876-7779 Panzem® EntreMed angiogenesis multiple myeloma Phase II 2-methoxyestradiol Rockville, MD inhibitor (240) 864-2600 (Orphan Drug) www.entremed.com patient speciﬁc Genzyme vaccine kidney cancer Phase I vaccine Cambridge, MA (800) 745-4447 PBL and TIL National Cancer Institute gene therapy melanoma Phase I transduced with Bethesda, MD NCI TRIAL anti-gp100 TCR (800) 4-CANCER PBL or TIL National Cancer Institute gene therapy melanoma Phase I transduced with Bethesda, MD NCI TRIAL retroviral vector; (800) 4-CANCER expressing anti- MART-1 TCR gene PEG-Intron® Schering-Plough interferon malignant melanoma Phase III peginterferon Kenilworth, NJ (908) 298-4000 alfa-2b peripheral blood National Cancer Institute gene therapy melanoma Phase I lymphocytes Bethesda, MD NCI TRIAL transduced with (800) 4-CANCER a gene encoding a chimeric T-cell receptor PG-CPT Cell Therapeutics colorectal cancer Phase II (CT-2106) Seattle, WA (206) 282-7100 PRO1762 Genentech soluble human cancer Phase I (Apo2L/TRIAL) South San Francisco, CA protein (650) 225-1000 Proleukin® Chiron interleukin non-Hodgkin’s lymphoma Phase I/II aldesleukin Emeryville, CA (800) CHIRON-8 (interleukin-2) ProMune™ Coley Pharmaceutical immune-based cutaneous T-cell Phase II CpG 7909 Wellesley, MA therapy lymphoma, malignant (781) 431-9000 melanoma, NSCLC

M EDICINES IN D EVELOPMENT Biotechnology 2004 13 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Prostvac®-VF Therion Biologics vaccine hormone refractory Phase II recombinant Cambridge, MA metastatic prostate (617) 876-7779 vaccinia virus cancer expressing PSA proteinase National Cancer Institute vaccine leukemia Phase I/II 3 peptide Bethesda, MD NCI TRIAL vaccine (800) 4-CANCER Provenge™ Dendreon vaccine early-stage and advanced Phase III Seattle, WA prostate cancer (206) 256-4545 PV701 National Cancer Institute attenuated bladder cancer Phase I Bethesda, MD virus N C I T RIAL Pro-Virus (800) 4-CANCER Gaithersburg, MD RadioTheraCIM YM Biosciences MAb glioma Phase I Mississauga, Ontario (905) 629-9761 Rituxan® Genentech MAb treatment of frontline Phase III completed rituximab South San Francisco, CA indolent and frontline (650) 225-1000 Biogen Idec aggressive non-Hodgkin’s Cambridge, MA lymphoma (see also autoimmune) ------treatment of indolent Phase III maintenance non-Hodgkin’s (650) 225-1000 lymphoma, relapsed chronic lymphocytic leukemia rV/rF-PSA National Cancer Institute vaccine prostate cancer Phase I/II (L155)-TRICOM Bethesda, MD NCI TRIAL (800) 4-CANCER SBIL-2 transduced National Cancer Institute gene therapy melanoma Phase I/II autologous TIL Bethesda, MD NCI TRIAL (800) 4-CANCER SGN-15 Seattle Genetics immuno- NSCLC Phase II Bothell, WA conjugate (425) 527-4000 SGN-30 Seattle Genetics MAb anaplastic large cell Phase II (Orphan Drug) Bothell, WA lymphoma, Hodgkin’s (425) 527-4000 disease SGN-40 Seattle Genetics MAb multiple myeloma Phase I Bothell, WA (425) 527-4000 SGN-00101 National Cancer Institute vaccine cervical cancer Phase I/II (HspE7) Bethesda, MD NCI TRIAL StressGen Biotechnologies (800) 4-CANCER Victoria, British Columbia SS1(dsFv)-PE38 National Cancer Institute immunotoxin cervical, head/neck, Phase I Bethesda, MD ovarian, pancreatic N C I T RIAL cancers, squamous (800) 4-CANCER cell cancer of the lung, mesothelioma TACI-lg Serono recombinant B-cell disorders in clinical trials Rockland, MA protein (see also autoimmune) (800) 283-8088

14 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Tarceva™ Genentech anti-EGFR NSCLC application erlotinib South San Francisco, CA submitted OSI Pharmaceuticals (650) 225-1000 Melville, NY (800) 572-1932 Roche (973) 235-5000 Nutley, NJ ------pancreatic cancer Phase III (650) 225-1000 (800) 572-1932 (973) 235-5000 T-cell therapy Cancer Therapeutics cellular cancer Phase II Thomasville, GA therapy (229) 224-6839 Telcyta™ Telik tumor-activated NSCLC, ovarian cancer Phase III TLK286 Palo Alto, CA prodrug (650) 845-7700 Telintra™ Telik myelo- myelodysplastic Phase II TLK199 Palo Alto, CA stimulant syndrome (650) 845-7700 TG1024 Transgene gene therapy solid tumors Phase I/II (adenovirus IL2) Strasbourg, France www. transgene.fr/us TG1042 Transgene gene therapy cutaneous lymphoma Phase II (adenovirus IFN Strasbourg, France www. gamma) transgene.fr/us TG4001 Transgene gene therapy cervical dysplasia Phase II (MVA HPV IL2) Strasbourg, France www. transgene.fr/us TG4010 Transgene gene therapy prostate cancer Phase II (MVA MUC1 IL2) Strasbourg, France www. transgene.fr/us TheraCIM YM Biosciences MAb head and neck cancer, Phase III Egf receptor MAb Mississauga, Ontario pediatric brain cancer (905) 629-9761 TNFerade™ GenVec gene therapy esophageal, pancreatic, Phase II Biologic Gaithersburg, MD rectal cancers (240) 632-0740 TroVax® BioMedica vaccine breast, colorectal, renal, Phase II San Diego, CA cancers Oxford BioMedica Oxford, UK vaccine for lung Corixa vaccine lung cancer Phase I cancer Seattle, WA (206) 366-3700 VEGF trap Aventis Pharmaceuticals anti- solid tumors Phase I/II Bridgewater, NJ angiogenesis (see also eye) (973) 394-6000 Regeneron Pharmaceuticals (914) 345-7400 Tarrytown, NY Velcade® Millennium small molecule multiple myeloma, solid Phase II bortezomib Pharmaceuticals tumors (800) 589-9005 for injection Cambridge, MA Vitaxin MedImmune MAb melanoma, prostate cancer Phase II anti-angiogenesis Gaithersburg, MD (see also autoimmune, skin) (301) 398-0000 MAb

M EDICINES IN D EVELOPMENT Biotechnology 2004 15 C ANCER AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Voraxaze™ Protherics recombinant high-dose methotrexate Phase III glucarpidase Brentwood, TN protein/enzyme toxicity (615) 327-1027 (Orphan Drug) ext. 4528 Xcellerated Xcyte Therapies cellular therapy non-Hodgkin’s lymphoma Phase II T-Cells™ Seattle, WA (206) 262-6200 ------CLL, multiple myeloma Phase I/II (206) 262-6200 Xyotax™ Cell Therapeutics NSCLC, ovarian Phase I/II/III Seattle, WA cancer (206) 282-7100

C ARDIOVASCULAR D ISEASE Product Product Development Name Sponsor Category Indication Status AC2592 (GLP-1) Amylin Pharmaceuticals late-stage congestive Phase II San Diego, CA heart failure (858) 552-2200 AC3056 Amylin Pharmaceuticals atherosclerosis-related Phase I San Diego, CA cardiovascular disease (858) 552-2200 Adentri™ Biogen Idec congestive heart failure Phase III adenosine A1 Cambridge, MA (617) 679-2000 antagonist BioByPass® GenVec gene therapy, coronary artery disease Phase II Angrogen Rockville, MD growth factor (240) 632-0740 therapeutic angiogenesis (VEGF) cell therapy Genzyme cell therapy ventricular restoration Phase II Cambridge, MA (800) 745-4447 cell transplantation GenVec cellular congestive heart failure Phase I therapy Gaithersburg, MD therapy (240) 632-0740 CETi-1 vaccine AVANT Immunotherapeutics vaccine cholesterol management Phase II Needham, MA (781) 433-0771 Deltavasc™ Valentis gene therapy intermittent claudication, Phase II Burlingame, CA peripheral arterial disease (650) 697-1900 ext. 257 GENERX™ Collateral Therapeutics gene therapy stable exertional angina Phase II/III San Diego, CA due to coronary artery (858) 794-3400 disease gene therapy Genzyme gene therapy peripheral arterial disease Phase I Cambridge, MA (800) 745-4447 ------coronary artery disease Phase I (800) 745-4447 ISIS 301012 Isis Pharmaceuticals antisense high cholesterol Phase I Carlsbad, CA (800) 679-ISIS Liprostin™ Endovasc peripheral vascular disease Phase II completed Montgomery, TX (936) 582-5920

16 M EDICINES IN D EVELOPMENT Biotechnology 2004 C ARDIOVASCULAR D ISEASE Product Product Development Name Sponsor Category Indication Status MLN 2222 Millennium recombinant vascular inﬂammation Phase I Pharmaceuticals fusion reduction of post-operative (800) 589-9005 Cambridge, MA protein events in coronary artery XOMA graft surgery Berkeley, CA NV1FGF Aventis Pharmaceuticals gene therapy peripheral vascular disease Phase I/II Bridgewater, NJ (973) 394-6000 pexelizumab Alexion Pharmaceuticals MAb acute myocardial Phase III Cheshire, CT infarction, cardiopulmonary (203) 272-2596 Procter & Gamble bypass Pharmaceuticals Mason, OH Resten-MP AVI BioPharma antisense cardiovascular restinosis Phase I Portland, OR (503) 227-0554 Resten-NG AVI BioPharma antisense cardiovascular restinosis Phase II completed Portland, OR (503) 227-0554 TP10 AVANT Immunotherapeutics recombinant adult and pediatric cardiac Phase II Needham, MA soluble surgery (781) 433-0771 receptor vascular Corantus Genetics gene therapy peripheral artery disease, Phase II endothelial Atlanta, GA refractory myocardial (404) 526-6200 growth factor 2 ischemia (VEGF.2)

D IABETES AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status Exenatide Amylin Pharmaceuticals type 2 diabetes application synthetic San Diego, CA submitted exendin-4 (858) 552-2200 Exenatide LAR Alkermes type 2 diabetes Phase II synthetic Cambridge, MA (858) 552-2200 exendin-4 Amylin Pharmaceuticals (long acting) San Diego, CA Exubera® Aventis Pharmaceuticals recombinant diabetes Phase III Bridgewater, NJ insulin Nektar Therapeutics San Carlos, CA Pﬁzer New York, NY ISIS 113715 Isis Pharmaceuticals antisense type 2 diabetes Phase II Carlsbad, CA (800) 679-ISIS NBI-6024 Neurocrine Biosciences peptide type 1 diabetes Phase II San Diego, CA therapeutic (858) 658-7600 vaccine NN304 Novo Nordisk recombinant treatment of diabetes Phase III (insulin detemir) Pharmaceuticals insulin mellitus (800) 727-6500 Princeton, NJ

M EDICINES IN D EVELOPMENT Biotechnology 2004 17 D IABETES AND R ELATED C ONDITIONS Product Product Development Name Sponsor Category Indication Status NN2211 Novo Nordisk secretagogue adjunct to diet and exercise Phase II Pharmaceuticals to improve glycemic control (800) 727-6500 Princeton, NJ and manage body weight in type 2 diabetes pimagedine Alteon diabetic overt Phase II/III Ramsey, NJ nephropathy completed (201) 934-5000 SomatoKine® Insmed growth factor diabetes Phase II IGF-1/IGFBP-3 Richmond, VA (see also growth) (804) 565-3022 Symlin® Amylin Pharmaceuticals human amylin type 1 and insulin-using application pramlintide San Diego, CA analog type 2 diabetes submitted acetate (858) 552-2200

D IGESTIVE D ISORDERS Product Product Development Name Sponsor Category Indication Status alicaforsen Isis Pharmaceuticals antisense Crohn’s disease Phase III Carlsbad, CA (800) 679-ISIS ------ulcerative colitis Phase II (800) 679-ISIS Antegren® Elan Pharmaceuticals MAb Crohn’s disease Phase III natalizumab South San Francisco, CA (see also neurologic) Humira Abbott Laboratories MAb Crohn’s disease Phase III adalimumab Abbott Park, IL (see also autoimmune, skin) (847) 936-1189 HuZAF™ Protein Design Labs MAb Crohn’s disease Phase II fontolizumab Fremont, CA (510) 574-1400 Insegia™ Aphton vaccine gastroesophageal reﬂux Phase II anti-gastrin 17 Miami, FL disease (GERD), www.aphton.com gastrointestinal ulcerations (see also cancer) kappaproet Serono antisense ulcerative colitis Phase II Rockland, MA inhibitor (800) 283-8088 Leukine® Berlex Laboratories colony Crohn’s disease Phase II sargramostim Montville, NJ stimulating (973) 487-2000 (GM-CSF) factor MLN-02 Genentech MAb Crohn’s disease, Phase II South San Francisco, CA inﬂammatory bowel (650) 225-1000 Millennium disease, ulcerative (800) 589-9005 Pharmaceuticals colitis Cambridge, MA Nuvion® Protein Design Labs MAb severe ulcerative colitis Phase I/II visilizumab Fremont, CA (510) 574-1400 OSI-461 OSI Pharmaceuticals selective Crohn’s disease Phase II Melville, NY apoptotic (see also cancer) (800) 572-1932 antineoplastic drug

18 M EDICINES IN D EVELOPMENT Biotechnology 2004 D IGESTIVE D ISORDERS Product Product Development Name Sponsor Category Indication Status tolevamer Genzyme polymer-based treatment of C. difﬁcile Phase II (toxin binder) Cambridge, MA toxin binder colitis (800) 745-4447

E YE C ONDITIONS Product Product Development Name Sponsor Category Indication Status AdPEDF GenVec gene therapy severe wet age-related Phase I Gaithersburg, MD macular degeneration (240) 632-0740 CA4P OXiGENE vascular neovascular age-related Phase I/II Watertown, MA targeting macular degeneration (617) 673-7800 agent (see also cancer) Lucentis™ Genentech antibody wet form of age-related Phase III ranibizumab South San Francisco, CA fragment macular degeneration (650) 225-1000 VEGF trap Aventis Pharmaceuticals anti- age-related macular Phase I/II Bridgewater, NJ angiogenesis degeneration (973) 394-6000 Regeneron Pharmaceuticals (see also cancer) (914) 345-7400 Tarrytown, NY Visudyne® QLT photosensitizer minimally classic age- Phase III verteporﬁn Vancouver, British Columbia related macular (604) 707-7000 degeneration

G ENETIC D ISORDERS Product Product Development Name Sponsor Category Indication Status Aryplase™ BioMarin Pharmaceutical enzyme mucopolysaccharidosis VI Phase III arylsulfantase B Novato, CA (MPS-VI) (415) 506-6777 (Orphan Drug) DX-88 Genzyme treatment of hereditary Phase II Cambridge, MA angioedema (800) 745-4447 GA-GCB Transkaryotic Therapies enzyme Gaucher disease Phase I/II (gene-activated Cambridge, MA replacement (617) 349-0200 glucerebrosidase) therapy HE2000 Hollis-Eden Pharmaceuticals cellular cystic ﬁbrosis Phase I San Diego, CA therapy (see also AIDS/HIV, (858) 587-9333 infectious) iduronate-2- Transkaryotic Therapies enzyme Hunter syndrome Phase III sulfatase Cambridge, MA replacement (617) 349-0200 (Orphan Drug) therapy MOLI 1901 Molichem Medicines cystic ﬁbrosis Phase II duramycin Chapel Hill, NC

M EDICINES IN D EVELOPMENT Biotechnology 2004 19 G ENETIC D ISORDERS Product Product Development Name Sponsor Category Indication Status Myozyme™ Genzyme enzyme treatment of Pompe Phase III alpha-glucosidase Cambridge, MA replacement disease (6 months and (800) 745-4447 (Orphan Drug) therapy younger) ------treatment of Pompe Phase II disease (3 years and (800) 745-4447 younger) Replagal™ Transkaryotic Therapies enzyme Fabry disease Phase III agalsidase alfa Cambridge, MA replacement (617) 349-0200 (Orphan Drug) therapy tgAAVCF Targeted Genetics gene therapy treatment of cystic Phase II (Orphan Drug) Seattle, WA ﬁbrosis (206) 623-7612

G ROWTH D ISORDERS Product Product Development Name Sponsor Category Indication Status Nutropin® Genentech recombinant idiopathic short stature application somatropin South San Francisco, CA human growth submitted (rDNA origin) for hormone (650) 225-1000 injectable Nutropin AQ® Genentech recombinant idiopathic short stature application somatropin South San Francisco, CA human growth submitted (rDNA origin) hormone (650) 225-1000 (liquid) SomatoKine® Insmed growth factor growth hormone Phase III IGF-1/IGFBP-3 Richmond, VA insensitivity syndrome (804) 565-3022 (Orphan Drug) (see also diabetes)

I NFECTIOUS D ISEASES Product Product Development Name Sponsor Category Indication Status 1018-ISS Dynavax Technologies immune-based hepatitis B prophylaxis Phase III Emeryville, CA therapy (see also respiratory, other) (510) 848-5100 ACTIVAX Antex Biologics vaccine prevention of travelers’ Phase II Gaithersburg, MD diseases (301) 590-0129 AG-702 Antigenics vaccine genital herpes (HSV-2) Phase I New York, NY (866) 805-8994 Albuferon™ Human Genome Sciences interferon chronic hepatitis C Phase I/II Rockville, MD www.hgsi.com Alferon N Hemispherx Biopharma interferon West Nile virus Phase II Injection® New Brunswick, NJ encephalitis (718) 670-1525 interferon alfa-n3 Philadelphia, PA AltaStaph™ NABI immune prevention of Phase I/II Rockville, MD globulin Staphylococcus aureus (301) 770-3099

20 M EDICINES IN D EVELOPMENT Biotechnology 2004 I NFECTIOUS D ISEASES Product Product Development Name Sponsor Category Indication Status Campyvax™ Antex Biologics cellular Campylobacter infections Phase II completed Campylobacter Gaithersburg, MD vaccine (301) 590-0129 vaccine Cervarix MedImmune recombinant prevention of Phase III HPV vaccine Gaithersburg, MD vaccine HPV infections (301) 398-0000 GlaxoSmithKline (see also cancer) (888) 825-5249 Philadelphia, PA Rsch. Triangle Park, NC CholeraGarde™ AVANT Immunotherapeutics vaccine cholera Phase II cholera vaccine Needham, MA (781) 433-0771 DNA vaccine Vical vaccine anthrax Phase I (anthrax) San Diego, CA (858) 646-1100 DNA vaccine Vical vaccine cytomegalovirus (CMV) Phase I (CMV) San Diego, CA (858) 646-1100 Doxovir™ Redox Pharmaceutical herpes simplex virus 1 Phase I completed New York, NY (HSV-1) (212) 543-4530 (see also AIDS) ------HSV-2, human Phase I papillomavirus (HPV), (212) 543-4530 ocular adenoviruses, STDs Epstein-Barr virus MedImmune recombinant prevention of Epstein-Barr Phase II vaccine Gaithersburg, MD vaccine virus infection (301) 417-0770 GlaxoSmithKline (cause of mononucleosis (888) 825-5249 Philadelphia, PA infection) Rsch. Triangle Park, NC Fendrix GlaxoSmithKline recombinant extra strength hepatitis B application extra strength Philadelphia, PA vaccine prophylaxis submitted hepatitis B Rsch. Triangle Park, NC (pre-hemodialysis and (888) 825-5249 vaccine hemodialysis patients) FlulNsure™ ID Biomedical vaccine prevention of inﬂuenza Phase II Bothell, WA virus (425) 482-2601 HCV vaccine Chiron vaccine hepatitis C Phase I Emeryville, CA (800) CHIRON-8

HE2000 Hollis-Eden cellular malaria Phase I/II Pharmaceuticals therapy (see also AIDS/HIV, (858) 587-9333 San Diego, CA genetic) Helivax™ Antex Biologics cellular Helicobacter pylori Phase I Helicobacter pylori Gaithersburg, MD vaccine infections (301) 590-0129 vaccine hepatitis E vaccine Genelabs Technologies recombinant hepatitis E prophylaxis Phase II Redwood City, CA vaccine (650) 369-9500 GlaxoSmithKline (888) 825-5249 Philadelphia, PA Rsch. Triangle Park, NC

M EDICINES IN D EVELOPMENT Biotechnology 2004 21 I NFECTIOUS D ISEASES Product Product Development Name Sponsor Category Indication Status HPV vaccine Merck vaccine prevention of cervical Phase III Whitehouse Station, NJ cancer and genital warts due to HPV infection (see also cancer) ISIS 14803 Isis Pharmaceuticals antisense hepatitis C Phase II Carlsbad, CA (800) 679-ISIS leishmania vaccine Corixa vaccine leishmaniasis Phase I Seattle, WA (206) 366-3700 LeukoScan® Immunomedics MAb, Fab´ diagnosis of osteomyelitis, application sulesomab Morris Plains, NJ fragment equivocal appendicitis submitted (973) 605-8200 meningococcal B Chiron vaccine meningitis B Phase II vaccine-geography Emeryville, CA (800) CHIRON-8 speciﬁc (New Zealand) Menjugate® Chiron vaccine meningitis C Phase III Emeryville, CA (800) CHIRON-8 Mosquirix GlaxoSmithKline recombinant malaria prevention Phase II malaria vaccine Philadelphia, PA vaccine (888) 825-5249 Rsch. Triangle Park, NC MPL® Corixa vaccine infectious diseases Phase III Seattle, WA adjuvant (see also respiratory) (206) 366-3700 multivalent (ACYW) Chiron vaccine meningitis Phase II meningococcal Emeryville, CA (800) CHIRON-8 vaccine PEG-alfacon-1 InterMune pegylated hepatitis C Phase I Brisbane, CA interferon (415) 466-2200 Pegasys® Roche interferon hepatitis B application pegylated interferon Nutley, NJ submitted alfa-2a (973) 235-5000 r-interferon beta Serono recombinant chronic hepatitis C in Phase III Rockland, MA protein Asian patients (800) 283-8088 Rotarix® AVANT Immunotherapeutics vaccine rotavirus in infants Phase III rotavirus Needham, MA (781) 433-0771 vaccine GlaxoSmithKline (888) 825-5249 Philadelphia, PA Rsch. Triangle Park, NC RotaTeq® Merck vaccine prevention of infant Phase III (rotavirus vaccine Whitehouse Station, NJ diarrhea and dehydration (800) 672-6372 antigen) due to rotavirus rPA102 VaxGen recombinant inhaled anthrax (pre- and Phase I/II (recombinant Brisbane, CA vaccine post-exposure (650) 624-1041 protective antigen) S. pneumoniae GlaxoSmithKline recombinant prevention of Phase I recombinant Philadelphia, PA vaccine S. pneumoniae in the (888) 825-5249 vaccine Rsch. Triangle Park, NC elderly

22 M EDICINES IN D EVELOPMENT Biotechnology 2004 I NFECTIOUS D ISEASES Product Product Development Name Sponsor Category Indication Status Simplirix GlaxoSmithKline recombinant genital herpes prophylaxis Phase III Philadelphia, PA vaccine (888) 825-5249 Rsch. Triangle Park, NC StaphVax® NABI vaccine prevention of Staphylococcus Phase III Rockville, MD aureus bacteremia (301) 770-3099 staphylococcal GlaxoSmithKline MAb prevention of Phase I antibodies Philadelphia, PA vaccine staphylococcal (888) 835-5249 MAb vaccine Rsch. Triangle Park, NC infections StreptAvax™ ID Biomedical vaccine diseases caused by group A Phase II group A Bothell, WA Streptococcus, including (425) 482-2601 Streptococcus necrotizing fasciitis, strep vaccine throat, rheumatic fever tifacogin Chiron tissue growth severe CAP Phase III (TFPI) Emeryville, CA factor pathway (800) CHIRON-8 inhibitor Ty800 AVANT Immunotherapeutics vaccine typhoid fever Phase I typhoid fever Needham, MA (781) 433-0771 vaccine vaccine for Corixa vaccine tuberculosis Phase I tuberculosis Seattle, WA (206) 366-3700 varicella zoster GlaxoSmithKline recombinant prevention of Phase I recombinant Philadelphia, PA vaccine varicella zoster (888) 835-5249 vaccine Rsch. Triangle Park, NC

N EUROLOGIC D ISORDERS Product Product Development Name Sponsor Category Indication Status Alzhemed™ Neurochem anti-amyloidotic Alzheimer’s disease Phase III Laval, Quebec (AB) agent Antegren® Elan Pharmaceuticals MAb multiple sclerosis Phase III natalizumab South San Francisco, CA (see also digestive) atexakin-α Serono recombinant peripheral neuropathy Phase II (r-IL-6) Rockland, MA protein (800) 283-8088 AV201 Avigen gene therapy Parkinson’s disease Phase I/II Alameda, CA (510) 748-7150 Campath® ILEX Oncology MAb multiple sclerosis Phase II alemtuzumab San Antonio, TX (973) 487-2000 CEP-1347 Cephalon signaling, Parkinson’s disease Phase II/III West Chester, PA MLK-receptor (610) 344-0200 tyrosine kinase inhibitor Cerebril™ Neurochem anti-amyloidotic hemorrhaghic stroke Phase II Laval, Quebec (AB) agent caused by cerebral amyloid angiopathy

M EDICINES IN D EVELOPMENT Biotechnology 2004 23 N EUROLOGIC D ISORDERS Product Product Development Name Sponsor Category Indication Status desmoteplase Forest Laboratories recombinant stroke Phase II New York, NY plasminogen activator GDNF Amgen glial cell Parkinson’s disease Phase II Thousand Oaks, CA derived (805) 447-1000 neurotrophic factor MLN519 Millennium small stroke Phase I completed Pharmaceuticals molecule (800) 589-9005 Cambridge, MA NBI-5788 Neurocrine Biosciences peptide multiple sclerosis Phase II San Diego, CA therapeutic (858) 658-7600 vaccine NGF antagonist Amgen nerve growth neuropathic pain Phase I Thousand Oaks, CA factor (805) 447-1000 phenserine AXONYX Alzheimer’s disease Phase II/III (acetylcholineslerase New York, NY (212) 666-7248 inhibitor-3rd generation) second generation Genzyme pain due to osteoarthritis Phase I Synvisc® Cambridge, MA (800) 666-7248 (hylan G-F20) Spheramine® Titan Pharmaceuticals cellular Parkinson’s disease Phase II allogeneic human South San Francisco, CA therapy (650) 244-4990 retinal pigment epithelial cells on gelatin microcarriers (Orphan Drug) Synvisc® Genzyme pain due to osteoarthritis Phase III (hylan G-F20) Cambridge, MA in the hip (800) 666-7248

R ESPIRATORY D ISORDERS Product Product Development Name Sponsor Category Indication Status 1018-ISS Dynavax Technologies immune-based asthma Phase II Emeryville, CA therapy (see also infectious, other) (510) 848-5100 332235 GlaxoSmithKline chronic obstructive Phase I (chemokine 2 Philadelphia, PA pulmonary disease (888) 825-5249 antagonist/IL8 Rsch. Triangle Park, NC (COPD) antagonist, oral) AVE-7279 Aventis Pharmaceuticals oligonucleotide asthma Phase I/II Bridgewater, NJ (973) 394-6000 Coley Pharmaceuticals Wellesley, MA CAIV-T MedImmune vaccine prevention of inﬂuenza Phase III Gaithersburg, MD (301) 398-0000

24 M EDICINES IN D EVELOPMENT Biotechnology 2004 R ESPIRATORY D ISORDERS Product Product Development Name Sponsor Category Indication Status CRX-675 Corixa TLR4 agonist seasonal allergic rhinitis Phase I Seattle, WA (206) 366-3700 daclizumab Protein Design Labs MAb asthma Phase II Fremont, CA (510) 574-1400 FluBIØk™ Protein Sciences vaccine prevention of inﬂuenza Phase III trivalent Meriden, CT (203) 686-0800, recombinant ext. 308 hemagglutinin inﬂuenza vaccine IL-4/13 trap Regeneron Pharmaceuticals interleukin asthma Phase I Tarrytown, NY (914) 345-7400 mepolizumab GlaxoSmithKline MAb asthma Phase II (anti-IL5 MAb) Philadelphia, PA (see also other) (888) 825-5249 Rsch. Triangle Park, NC MPL® Corixa vaccine allergies Phase III vaccine adjuvant Seattle, WA adjuvant (see also infectious) (206) 366-3700 Numax MedImmune MAb prevention of respiratory Phase II Gaithersburg, MD syncytial virus (301) 398-0000 RSV subunit Wyeth continuous prevention of respiratory Phase II vaccine Philadelphia, PA cell line syncytial virus-mediated vaccine lower respiratory disease in the elderly and at-risk children RSV vaccine, Wyeth continuous prevention of respiratory Phase II live, attenuated Philadelphia, PA cell line syncytial virus-mediated vaccine lower respiratory disease in infants Xolair® Genentech MAb pediatric asthma Phase III omalizumab South San Francisco, CA (see also other) (650) 225-1000 Novartis Pharmaceuticals East Hanover, NJ Tanox Houston, TX

S KIN D ISORDERS Product Product Development Name Sponsor Category Indication Status Dimericine AGI Dermatics protection against actinic Phase III T4N5 liposome Freeport, NY keratoses in patients with (516) 868-9026 lotion xeroderma pigmentosa eculizumab Alexion Pharmaceuticals MAb dermatomyositis Phase II (Orphan Drug) Cheshire, CT (see also autoimmune) (203) 272-2596 Humira Abbott Laboratories MAb psoriasis Phase II adalimumab Abbott Park, IL (see also autoimmune, (847) 936-1189 digestive)

M EDICINES IN D EVELOPMENT Biotechnology 2004 25 S KIN D ISORDERS Product Product Development Name Sponsor Category Indication Status Ontak® Ligand Pharmaceuticals fusion protein severe psoriasis Phase II denileukin diftitox San Diego, CA (see also cancer) (858) 550-7500 r-TBP-1 Serono recombinant psoriasis Phase III (onercept) Rockland, MA protein (800) 283-8088 tadekinig-α Serono recombinant psoriasis Phase II (IL-18bp) Rockland, MA protein (see also autoimmune) (800) 283-8088 Vitaxin MedImmune MAb psoriasis Phase II anti-angiogenesis Gaithersburg, MD (see also autoimmune, (301) 398-0000 MAb cancer)

T RANSPLANTATION Product Product Development Name Sponsor Category Indication Status CIS Chiron inhaled acute lung Phase III Emeryville, CA cyclosporine transplantation (800) CHIRON-8 rejection CTLA4Ig Bristol-Myers Squibb recombinant immunosuppression Phase II Princeton, NJ soluble (212) 546-4000 receptor Thymoglobulin® Genzyme polyclonal bone marrow transplant Phase II anti-thymocyte Cambridge, MA antibody rejection (888) 764-7828 globulin ------(rabbit) liver transplant rejection Phase II (888) 764-7828

O THER Product Product Development Name Sponsor Category Indication Status 1018-ISS Dynavax Technologies immune-based ragweed allergy Phase II Emeryville, CA therapy (see also infectious, (510) 848-5100 respiratory) AC137 Amylin Pharmaceuticals obesity Phase II San Diego, CA (858) 552-2200 AC162352 Amylin Pharmaceuticals obesity Phase I San Diego, CA (858) 552-2200 ALX-0600 NPS Pharmaceuticals recombinant short bowel syndrome Phase III Salt Lake City, UT DNA (801) 583-4939 AMG162 Amgen recombinant osteoporosis Phase III Thousand Oaks, CA protein (see also cancer) (805) 447-1000 Axokine® Regeneron Pharmaceuticals obesity Phase III Tarrytown, NY (914) 345-7400

26 M EDICINES IN D EVELOPMENT Biotechnology 2004 O THER Product Product Development Name Sponsor Category Indication Status Fibrillex™ Neurochem anti-amyloidosis AA amyloidosis Phase II/III NC-503 Laval, Quebec (AA) agent (Orphan Drug) human liver cell Vesta Therapeutics cellular therapy cirrhosis of the liver, Phase I therapy Durham, NC end-stage liver disease Kineret® Amgen recombinant osteoarthritis Phase II anakinra Thousand Oaks, CA human protein (805) 447-1000 Luveris® Serono recombinant follicular development in application lutropin alfa for Rockland, MA protein infertile hypogonadotropic submitted injection hypogonadal women with (800) 283-8088 profound luteinizing hormone deﬁciency mepolizumab GlaxoSmithKline MAb hypereosinophillic Phase II (anti-IL5 MAb) Philadelphia, PA syndrome (888) 825-5249 Rsch. Triangle Park, NC (see also respiratory) PHP Curacyte nitric shock associated with SIRS, Phase III pyridoxalated Chapel Hill, NC oxide (systemic inﬂammatory (919) 405-4002 hemoglobin scavenger response syndrome), polyoxyethylene nitric oxide-induced shock Preos™ NPS Pharmaceuticals recombinant post-menopausal Phase III completed recombinant Salt Lake City, UT human osteoporosis (801) 583-4939 human parathyroid parathyroid hormone hormone (rhPTH) Puricase® Savient Pharmaceuticals recombinant symptomatic gout that is Phase II PEG-uricase East Brunswick, NJ enzyme unresponsive to (800) 284-2480 (Orphan Drug) conventional treatments tissue repair cells Aastrom Biosciences cellular tibial non-union Phase II (adult bone Ann Arbor, MI therapy fractures (734) 930-5555 marrow-derived stem cells) XMP 629 XOMA mild to moderate Phase II Berkeley, CA acne (800) 246-9462 Xolair® Genentech MAb peanut allergy Phase II omalizumab South San Francisco, CA (see also respiratory) (650) 225-1000 Novartis Pharmaceuticals East Hanover, NJ Tanox Houston, TX

The content of this survey has been obtained through government and industry sources based on the latest information. Survey current as of August 27, 2004. The information may not be comprehensive. For more speciﬁc information about a particular product, contact the individual company directly. The entire series of “Medicines in Development” is available on PhRMA’s web site. PhRMA Internet address: www.phrma.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2004 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

M EDICINES IN D EVELOPMENT Biotechnology 2004 27 Approved Biotechnology Products

Product Product Name Company Category Indication Actimmune® InterMune Pharmaceuticals interferon management of chronic granulomatous disease interferon Palo Alto, CA (December 1990); osteopetrosis (February 2000) gamma-1b Activase® Genentech tissue acute myocardial infarction (November 1987); alteplase, South San Francisco, CA plasminogen acute massive pulmonary embolism (June 1990); recombinant activator acute myocardial infarction (accelerated infusion) (April 1995); ischemic stroke within 3 to 5 hours of symptom onset (June 1996) AcuTect™ Berlex Laboratories peptide scintigraphic imaging of acute venous thrombosis Tc-99m apcitide Montville, NJ in the lower extremities of patients who have signs and symptoms of acute venous thrombosis (September 1998) Adagen® Enzon enzyme treatment of severe combined immunodeficiency Injection Bridgewater, NJ replacement disease (SCID) (March 1990) pegademase bovine therapy Aldurazyme® BioMarin Pharmaceutical enzyme treatment of mucopolysaccharidosis-I (MPS-I) laronidase for Novato, CA replacement (May 2003) injection Genzyme therapy (Orphan Drug) Cambridge, MA Alferon N Hemispherx Biopharma interferon genital warts (October 1989) Injection® New Brunswick, NJ interferon alfa-n3 Philadelphia, PA Amevive® Biogen Idec fusion protein psoriasis (January 2003) alefacept Cambridge, MA Apligraf™ Novartis Pharmaceuticals cell/tissue treatment of venous leg ulcers (May 1998) graftskin East Hanover, NJ therapy Aranesp® Amgen recombinant treatment of anemia in chronic renal failure darbepoetin alfa Thousand Oaks, CA protein (September 2001); treatment of chemotherapy- induced anemia (July 2002) Argatroban GlaxoSmithKline heparin-induced thrombocytopenia (HIT) Philadelphia, PA syndrome (June 2000) Rsch. Triangle Park, NC Texas Biotechnology Houston, TX Avastin™ Genentech MAb in combination with intravenous 5-fluorouracil- bevacizumab South San Francisco, CA based chemotherapy as a treatment for patients with first-line—or previously untreated— metastatic cancer of the colon and rectum (February 2004) Avonex® Biogen interferon relapsing multiple sclerosis (May 1996) interferon beta-1a Cambridge, MA BeneFIX™ Wyeth clotting treatment of hemophilia B (February 1997) recombinant Philadelphia, PA factor human factor IX

28 M EDICINES IN D EVELOPMENT Biotechnology 2004 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Betaseron® Berlex Laboratories interferon relapsing, remitting multiple sclerosis (July 1993) recombinant Montville, NJ interferon beta-1b Chiron Emeryville, CA Bexxar® Corixa radio- low-grade and transformed low-grade tositumomab, Seattle, WA immunotherapy non-Hodgkin’s lymphoma (June 2003) iodine GlaxoSmithKline MAb I 131 tositumomab Philadelphia, PA Rsch. Triangle Park, NC BioTropin™ Bio-Technology General human growth hormone deficiency in children human growth Iselin, NJ growth (May 1995) hormone hormone Campath® Berlex Laboratories MAb treatment of B-cell chronic lymphocytic leukemia alemtuzumab Montville, NJ (B-CLL) in patients who have been treated with ILEX Oncology alkylating agents and who have failed San Antonio, TX fludarabine therapy (May 2001) Carticel® Genzyme autologous repair of symptomatic cartilaginous defects autologous Cambridge, MA cell of the femoral condyle (medial, lateral, or cultured therapy trochlear) caused by acute or repetitive trauma chondrocytes (August 1997) CEA-Scan® Immunomedics monoclonal presence, location and detection of recurrent technetium-99m- Morris Plains, NJ antibody and metastatic colorectal cancer (June 1996) arcitumomab (MAb), Fab´ fragment Cerezyme® Genzyme enzyme treatment of type 1 Gaucher disease imiglucerase for Cambridge, MA replacement (May 1994) injection therapy Comvax™ Merck recombinant vaccination of infants beginning at two months Haemophilus b Whitehouse Station, NJ vaccine of age against both invasive Haemophilus conjugate influenzae type b diseases (Hib) and hepatitis B (meningococcal (October 1996) protein conjugate) and hepatitis b recombinant vaccine DACS™ SC Dendreon cell/tissue rescue therapy following high-dose stem cell Seattle, WA therapy chemotherapy (August 1999) enrichment device Elitek® Sanofi-Synthelabo recombinant prophylaxis for chemotherapy-related rasburicase New York, NY enzyme hyperuricemia, treatment of cancer-related hyperuricemia (July 2002) Enbrel® Amgen recombinant moderate to severe active rheumatoid arthritis etanercept Thousand Oaks, CA soluble (November 1998); moderate to severe active Wyeth receptor juvenile rheumatoid arthritis (May 1999); Philadelphia, PA disease modification of active rheumatoid arthritis, ankylosing spondylitis (July 2003); psoriatic arthritis (August 2003); psoriasis (April 2004)

M EDICINES IN D EVELOPMENT Biotechnology 2004 29 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Engerix-B® GlaxoSmithKline recombinant hepatitis B (September 1989) hepatitis B vaccine Philadelphia, PA vaccine (recombinant) Rsch. Triangle Park, NC EPOGEN® Amgen erythropoietin treatment of anemia associated with chronic renal Epoetin alfa Thousand Oaks, CA failure, including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovir®-treated HIV- infected patients (June 1989); treatment of anemia caused by chemotherapy in patients with non- myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996); anemia in children with chronic renal failure who are currently undergoing dialysis (November 1999) Fabrazyme® Genzyme enzyme treatment of Fabry disease (April 2003) agalsidase beta Cambridge, MA replacement (Orphan Drug) therapy FluMist™ MedImmune vaccine prevention of influenza A & B (June 2003) influenza vaccine Gaithersburg, MD Follistim® Organon recombinant infertility (September 1997) recombinant West Orange, NJ hormone follicle-stimulating hormone Fortéo™ Eli Lilly recombinant osteoporosis (December 2002) teriparatide Indianapolis, IN DNA origin injection rDNA origin Fuzeon® Roche peptide fusion HIV infection/AIDS (March 2003) enfuvirtide Nutley, NJ inhibitor Trimeris Durham, NC Genotropin® Pfizer human short stature in children due to growth hormone somatropin New York, NY growth deficiency (August 1995); growth failure due to (rDNA origin) hormone Prader-Willi syndrome (June 2000); long-term for injection treatment of growth failure in children born small for gestational age (July 2001) Geref® Serono growth factor evaluation of the ability of the somatotroph of human growth Rockland, MA the pituitary gland to secrete growth hormone hormone- (December 1990); pediatric growth hormone releasing factor deficiency (October 1997) GlucaGen® Novo Nordisk recombinant treatment of hypoglycemia and for use as a glucagon Pharmaceuticals human diagnostic aid (June 1998) (rDNA origin) Princeton, NJ protein for injection Gonal-F® Serono recombinant female infertility (September 1997) recombinant human Rockland, MA fertility follicle-stimulating hormone hormone (r-FSH)

30 M EDICINES IN D EVELOPMENT Biotechnology 2004 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Helixate® FS Aventis Behring clotting treatment of hemophilia A (June 2000) antihemophilic King of Prussia, PA factor factor (recombinant) Herceptin® Genentech MAb treatment of HER2 overexpressing metastatic trastuzumab South San Francisco, CA breast cancer (September 1998) Humalog® Eli Lilly recombinant diabetes (October 1982) insulin lispro Indianapolis, IN insulin Humatrope® Eli Lilly human human growth hormone deﬁciency in children somatropin Indianapolis, IN growth (March 1987) (rDNA origin) hormone for injection Humira® Abbott Laboratories MAb rheumatoid arthritis (December 2002) adalimumab Abbott Park, IL Humulin® Eli Lilly recombinant diabetes (October 1982) human insulin Indianapolis, IN insulin (recombinant DNA origin) Infergen® Amgen interferon treatment of chronic hepatitis C viral infection interferon alfacon-1 Thousand Oaks, CA (October 1997) Intron® A Schering-Plough interferon hairy cell leukemia (June 1986); genital warts interferon alfa-2b Kenilworth, NJ (June 1988); AIDS-related Kaposi’s sarcoma (recombinant) (November 1988); hepatitis C (February 1991); hepatitis B (July 1992); malignant melanoma (December 1995); follicular lymphoma in conjunction with chemotherapy (November 1997) Kineret® Amgen recombinant signs and symptoms of rheumatoid arthritis anakinra Thousand Oaks, CA protein (November 2001) KoGENate® Bayer clotting treatment of hemophilia A (February 1993) antihemophiliac West Haven, CT factor factor (recombinant) KoGENate-FS Bayer clotting hemophilia A (June 2000) rFVIII West Haven, CT factor Leukine™ Berlex Laboratories colony autologous bone marrow transplantation (March sargramostim Montville, NJ stimulating 1991); neutropenia resulting from chemotherapy (GM-CSF) factor in acute myelogenous leukemia (September 1995); allogeneic bone marrow transplantation (November 1995); peripheral blood progenitor cell mobilization and transplantation (December 1995) LYMErix™ GlaxoSmithKline vaccine prevention of Lyme disease (December 1998) Lyme disease Philadelphia, PA vaccine Rsch. Triangle Park, NC (recombinant OspA)

M EDICINES IN D EVELOPMENT Biotechnology 2004 31 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Mylotarg™ Wyeth MAb treatment of patients 60 years and older in gemtuzumab Philadelphia, PA first relapse with CD33-positive acute myeloid ozogamicin for leukemia (AML) who are not considered injection candidates for cytotoxic chemotherapy (May 2000) Natrecor® Scios recombinant acute decompensated congestive heart failure nesiritide Sunnyvale, CA human (August 2001) peptide Neulasta® Amgen colony chemotherapy-induced neutropenia pegfilgrastim Thousand Oaks, CA stimulating (January 2002) factor Neumega® Wyeth MAb prevention of severe chemotherapy-induced oprelvekin Philadelphia, PA thrombocytopenia (November 1997) NEUPOGEN® Amgen colony chemotherapy-induced neutropenia (February filgrastim Thousand Oaks, CA stimulating 1991); autologous or allogeneic bone marrow (rG-CSF) factor transplantation (June 1994); chronic severe neutropenia (December 1994); support peripheral blood progenitor cell transplantation (December 1995); acute myelogenous leukemia (April 1998) Norditropin® Novo Nordisk human treatment of growth failure in children due to somatropin Pharmaceuticals growth inadequate growth hormone secretion (May 1995) (rDNA origin) Princeton, NJ hormone for injection Novolin® 70/30 Novo Nordisk recombinant insulin-dependent diabetes mellitus (June 1991) 70% NPH human Pharmaceuticals insulin insulin isophane Princeton, NJ suspension & 30% regular, human insulin injection (recombinant DNA origin) Novolin® L Novo Nordisk recombinant insulin-dependent diabetes mellitus (June 1991) Lente®, human Pharmaceuticals insulin insulin zinc Princeton, NJ suspension (recombinant DNA origin) Novolin® N Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1991) NPH, human Pharmaceuticals insulin insulin isophane Princeton, NJ suspension (recombinant DNA origin) Novolin® R Novo Nordisk recombinant insulin-dependent diabetes mellitus (June 1991) regular, human Pharmaceuticals insulin insulin injection Princeton, NJ (recombinant DNA origin)

32 M EDICINES IN D EVELOPMENT Biotechnology 2004 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication NovoLog® Novo Nordisk recombinant treatment of adult diabetes mellitus (June 2000) insulin aspart Pharmaceuticals insulin (rDNA origin) Princeton, NJ injection NovoLog® Novo Nordisk recombinant treatment of diabetes mellitus (November 2001) Mix 70/30 Pharmaceuticals insulin 70% insulin aspart Princeton, NJ (rDNA origin) protamine suspension and 30% insulin aspart (rDNA origin) injection NovoSeven® Novo Nordisk recombinant treatment of bleeding episodes in hemophilia A coagulation Pharmaceuticals human or B patients with inhibitors to factor VIII or factor VIIa Princeton, NJ protein factor IX (March 1999) (recombinant) Nutropin® Genentech recombinant growth failure in children due to chronic renal somatropin South San Francisco, CA human insufficiency, growth hormone inadequacy in (rDNA origin) growth children (March 1994); Turner’s syndrome for injection hormone (December 1996); growth hormone inadequacy in adults (December 1997) Nutropin AQ™ Genentech recombinant growth failure in children due to chronic renal somatropin South San Francisco, CA human insufficiency, growth hormone inadequacy in (rDNA origin) growth children (December 1995); Turner’s syndrome (liquid) hormone (December 1996); growth hormone inadequacy in adults (December 1997) OncoScint® CYTOGEN MAb detection, staging and follow-up of colorectal CR/OV Princeton, NJ and ovarian cancers (December 1992) satumomab pendetide Oncospar® Enzon first-line treatment of acute lymphoblastic PEG-L- Bridgewater, NJ leukemia (February 1994) asparaginase Ontak Ligand Pharmaceuticals fusion persistant or recurrent cutaneous T-cell lymphoma denileukin San Diego, CA protein (February 1999) diftitox ORTHOCLONE Ortho Biotech MAb reversal of acute kidney transplant rejection OKT®3 Raritan, NJ (June 1991); reversal of heart and liver transplant muromonab-CD3 rejection (June 1993) Ovidrel® Prefilled Serono recombinant induction of final follicular maturation and early Syringe Rockland, MA protein luteinization (October 2003) choriogonadotropin alfa injection Pegasys® Roche interferon chronic hepatitis C (December 2002) peginterferon Nutley, NJ alfa-2a

M EDICINES IN D EVELOPMENT Biotechnology 2004 33 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Pegasys® Roche interferon chronic hepatitis C (December 2002) pegylated interferon Nutley, NJ alfa-2a and ribivirin combination PEG-Intron® Schering-Plough interferon hepatitis C (August 2001) peginterferon Kenilworth, NJ alfa-2b PROCRIT® Ortho Biotech erythropoietin treatment of anemia associated with chronic renal epoetin alfa Raritan, NJ failure, including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovir®-treated HIV- infected patients (December 1990); treatment of anemia caused by chemotherapy in patients with non-myeloidmalignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996); anemia in children with chronic renal failure who are currently undergoing dialysis (July 1999) [PROCRIT ® was approved for marketing under Amgen’s epoetin alfa PLA. Amgen manufactures the product for Ortho Biotech.] Under an agreement between the two companies, Amgen licensed to Ortho Pharmaceutical the U.S. rights to epoetin alfa for indications for human use excluding dialysis and diagnostics. Proleukin® Chiron interleukin renal cell carcinoma (May 1992); metastatic aldesleukin Emeryville, CA melanoma (January 1998) (interleukin-2) ProstaScint® CYTOGEN MAb detection, staging and follow-up of prostate capromab Princeton, NJ adenocarcinoma (October 1996) pentetate Protropin® Genentech human human growth hormone deficiency in children somatrem South San Francisco, CA growth (October 1985) for injection hormone Pulmozyme® Genentech recombinant cystic fibrosis (December 1993); management dornase alpha, South San Francisco, CA DNase of advanced cystic fibrosis (December 1996) recombinant Raptiva™ Genentech MAb chronic moderate to severe plaque psoriasis efalizumab South San Francisco, CA (October 2003) XOMA Berkeley, CA Rebetron™ Schering-Plough interferon treatment of chronic hepatitis C in patients who ribavirin/interferon Kenilworth, NJ have relapsed following alpha interferon therapy alfa-2b, (June 1998); treatment of chronic hepatitis C in combination patients with compensated liver disease previ- therapy ously untreated with alpha interferon therapy (December 1999) Rebif® Serono interferon relapsing forms of multiple sclerosis interferon beta-1a Rockland, MA (March 2002)

34 M EDICINES IN D EVELOPMENT Biotechnology 2004 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication recombinant Wyeth growth factor bone and tissue repair human bone Philadelphia, PA morphogenetic protein-2/ Absorbable Collagen Sponge (rhBMP-2/ACS) Recombinate™ Baxter Healthcare clotting prevention and control of bleeding episodes antihemophilic Deerfield, IL factor in patients with hemophilia A (December 1992) factor recombinant Wyeth (rAHF) Philadelphia, PA RECOMBIVAX HB® Merck recombinant hepatitis B prevention (July 1986) hepatitis B vaccine Whitehouse Station, NJ vaccine (recombinant) ReFacto® Wyeth clotting hemophilia A (March 2000) antihemophilic Philadelphia, PA factor factor VIII (recombinant) Refludan™ Berlex Laboratories recombinant heparin-induced thrombocytopenia type II lepirudin Montville, NJ anticoagulant (March 1998) [rDNA] for injection Regranex® Ortho-McNeil growth factor chronic diabetic ulcers (December 1997) becaplermin Pharmaceuticals (recombinant Raritan, NJ human platelet- derived growth factor-BB) Remicade™ Centocor MAb short-term use in Crohn’s disease (August 1998); infliximab Malvern, PA reduction of signs and symptoms in rheumatoid arthritis (November 1999); inhibit the progression of structural damage in patients with rheumatoid arthritis (January 2001); improve physical function in patients with rheumatoid arthritis (February 2002); long-term remission-level control of Crohn’s disease (July 2002) ReoPro® Centocor MAb anti-platelet prevention of blood clots in the abciximab Malvern, PA setting of high-risk percutaneous transluminal Eli Lilly coronary angioplasty (December 1994); refrac- Indianapolis, IN tory unstable angina when percutaneous coronary intervention is planned (November 1997) Retavase® Centocor tissue treatment of acute myocardial infarction reteplase Malvern, PA plasminogen (October 1996) factor

M EDICINES IN D EVELOPMENT Biotechnology 2004 35 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Rituxan® Genentech MAb treatment of relapsed or refractory low-grade or ritiximab South San Francisco, CA follicular CD20-positive B-cell non-Hodgkin’s Biogen Idec lymphoma (November 1997); retreatment of Cambridge, MA patients who have relapsed following initial Rituxan treatment, eight week doses (compared to original four), and treatment of bulky disease (April 2001) Roferon®-A Roche interferon hairy cell leukemia (June 1986); AIDS-related interferon alfa-2a, Nutley, NJ Kaposi’s sarcoma (November 1988); chronic recombinant myelogenous leukemia (November 1995); hepatitis C (November 1996) Saizen® Serono human pediatric growth hormone deﬁciency somatropin Rockland, MA growth (October 1996) (rDNA origin) hormone for injection Serostim™ Serono human treatment of AIDS-associated catabolism/ somatropin Rockland, MA growth wasting (August 1996); pediatric HIV failure to (rDNA origin) hormone thrive (February 1998) for injection Simulect® Novartis Pharmaceuticals MAb prevention of renal transplant rejection basiliximab East Hanover, NJ (May 1998) Synagis® Abbott Laboratories MAb respiratory syncytial virus (June 1998) palivizumab Abbott Park, IL Medlmmune Gaithersburg, MD Thymoglobulin® SangStat polyclonal prevention of kidney transplant rejection thymocyte globulin Menlo Park, CA antibody (December 1998) (rabbit) Thyrogen® Genzyme recombinant thyroid cancer follow-up (November 1998) thyrotropin alfa Cambridge, MA hormone for injection (diagnostic) TNKase™ Genentech thrombolytic acute myocardial infarction (June 2000) tenecteplase South San Francisco, CA Trisenox® Cell Therapeutics acute promyelocytic leukemia arsenic trioxide Seattle, WA (September 2000) Velosulin® BR Novo Nordisk recombinant treatment of diabetes mellitus (July 1999) buffered regular Pharmaceuticals insulin human insulin Princeton, NJ injection (rDNA origin)

36 M EDICINES IN D EVELOPMENT Biotechnology 2004 A PPROVED B IOTECHNOLOGY P RODUCTS Product Product Name Company Category Indication Verluma® DuPont Pharmaceuticals MAb detection of small-cell lung cancer (August 1996) nofetumomab Billerica, MA Visudyne® QLT photosensitizer minimally classic age-related macular verteporﬁn Vancouver, British Columbia degeneration (April 2000) Vitravene® Ciba Vision antisense treatment of cytomegalovirus retinitis in patients fomiviren sodium Duluth, GA with AIDS (August 1998) injectable Isis Pharmaceuticals Carlsbad, CA Xifaxan™ Salix Pharmaceuticals traveler’s diarrhea (May 2004) ritaximin Raleigh, NC Xigris™ Eli Lilly recombinant severe sepsis (November 2001) drotrecogin alfa Indianapolis, IN activated (activated) protein C Xolair® Genentech MAb treatment of moderate to severe allergy-related omalizumab South San Francisco, CA asthma (12 years and older) (June 2003) Novartis Pharmaceuticals East Hanover, NJ Tanox Houston, TX Zenapax® Roche MAb prophylaxis of acute kidney transplant rejection daclizumab Nutley, NJ (December 1997) Protein Design Labs Fremont, CA Zevalin™ IDEC Pharmaceuticals MAb treatment of relapsed or refractory low grade, ibritumomab San Diego, CA follicular, or transformed B-cell non-Hodgkin’s tiuxetan lymphoma (February 2002) Zorbtive™ Serono recombinant for patients with short bowel syndrome somatropin Rockland, MA protein requiring specialized nutritional support [rDNA origin] (December 2003) for injection

M EDICINES IN D EVELOPMENT Biotechnology 2004 37 G LOSSARY

actinic keratoses—Roughness and amyotrophic lateral sclerosis (ALS)— application submitted—Application thickening of the skin caused by Also known as Lou Gehrig’s disease, for marketing has been submitted to overexposure to the sun’s ultraviolet the most common of the motor the Food and Drug Administration rays. It can degenerate into a skin neuron diseases, a group of rare (FDA). cancer called squamous cell carci- disorders in which the nerves that autoimmune disorders—Diseases, noma. control muscular activity degenerate such as type 1 diabetes, rheumatoid within the brain and spinal cord adenocarcinoma—Malignant tumor arthritis, and multiple sclerosis, causing weakness and wasting of derived from a gland or glandular caused by the body producing an the muscles. tissue. immune response against its own angioedema—Swelling of the tissues. The cause of autoimmune adipose redistribution syndrome, mucous membranes, tissues beneath diseases is unknown, but it appears HIV-associated (HARS)—Patients the skin, or an internal organ due to that there is an inherited predisposi- with HARS, a subset of HIV-associ- an allergic reaction. tion to develop them in many cases. ated lipodystrophy, experience abnormal, pathological accumula- angiogenesis—The formation of new autologous (transfusion; transplan- tion of adipose tissue, which may be blood vessels, which is a process tation)—Autologous refers to a graft present with or without fat depletion controlled by certain chemicals pro- in which the donor and recipient are and/or metabolic abnormalities. In duced in the body. A chemical that the same individual. general, HARS patients accumulate signals this process to stop is B- and T-cell lymphomas—Cancers excess visceral adipose tissue in the referred to as an angiogenesis caused by proliferation of the two abdomen or may develop a pad of inhibitor. Cancer spreads by the for- principal types of white blood cells fat on the upper back commonly mation of new blood vessels, which —B- and T-lymphocytes. known as a “buffalo hump.” Unlike supply the cancer cells with oxygen the excess subcutaneous fat seen in and nutrients, helping the cells to biotechnology—The collection of obesity, visceral adipose tissue lies grow, invade nearby tissue, and industrial processes that involve the deep within the abdominal cavity, spread to other areas of the body. use of biological systems. For some placing patients at increased risk for Scientists are studying ways to stop of the industries, these processes metabolic abnormalities. angiogenesis, in the hope that involve the use of genetically engi- angiogenesis inhibitors will be able neered organisms. For the purpose of adjunct—An auxiliary treatment that to prevent the growth of cancer by this chart, only those products that is secondary to the main treatment. blocking the formation of new involve recombinant DNA, mono- adjuvant—Substance or drug that blood vessels. clonal antibody/hybridoma, continu- aids another substance in its action. ous cell lines, cellular therapy and angioplasty—A technique to open gene therapy technology are included. AIDS—Acquired immune deﬁciency up blocked coronary arteries with syndrome. a catheter tube. cachexia—Profound and marked state of general ill health and malnutri- allogeneic (transplantation)—Refers ankylosing spondylitis—An inﬂam- tion, usually characterized by severe to having cell types that are distinct matory disorder of unknown cause weight loss. and cause reactions in the immune that primarily affects the spine. The system. vertebrae may fuse together and Campylobacter infections— Gastrointestinal tract or blood amyloidosis—A disease in which form a rigid back that is impossible infections caused by Campylobacter amyloid, an unusual protein that to bend. The arthritis may involve bacteria. The most common form of normally isn’t present in the body, large joints, such as the hip. Campylobacter infection is gastroen- accumulates in various tissues. There antisense—An antisense drug is the teritis. Others are traveler’s diarrhea are many forms of the disease. In mirror or complementary image of and bacteremia. primary amyloidosis, the cause isn’t a small segment of messenger RNA known, but it is associated with (mRNA), the substance that carries CEA—Carcinoembryonic antigen abnormalities of plasma cells. In instructions (“sense”) from the genes found in the blood of patients suffer- secondary amyloidosis, the disease to the cell’s protein-making machin- ing from cancer of the colon and is secondary to another disease, such ery. The antisense drug readily binds some other diseases that is otherwise as tuberculosis. A third form is to the mRNA strand, keeping it from found in fetal gut tissue. hereditary and affects nerves and transmitting its instructions to the cell, cerebral amyloid angiopathy—A certain organs. and thus inhibiting the production condition in which there is a depo- of an unwanted protein. sition of amyloid (insoluble protein)

38 M EDICINES IN D EVELOPMENT Biotechnology 2004 G LOSSARY in the walls of the arteries supplying neurological disorder characterized genital herpes (herpes simplex 2)— the brain, resulting in an increased by progressive weakness and A strain of herpes virus that may lie risk of dementia or intracerebral impaired sensory function in the dormant in nerve tissue and can be hemorrhage. This condition is a com- legs and arms. The disorder, which reactivated to produce painful sores plication of primary amyloidosis. is sometimes called chronic relaps- of the anus or genitals. ing polyneuropathy, is caused by chlamydial infections—Chlamydiae germ cell tumors—These tumors damage to the myelin sheath (the are a group of microorganisms that typically begin in the reproductive fatty covering that wraps around and cause various infectious diseases in (germ) cells of the body. They most protects nerve fibers) of the periph- humans and animals. The most often occur in the testicles of young eral nerves. Although it can occur at important impact of the strain men, but they can also develop in any age and in both genders, CIDP Chlamydia trachomatis is its role as the ovaries of women. If these is more common in young adults a cause of nonspecific urethritis, or tumors originate outside the testicles and in men more so than women. nongonococcal genital infection. or ovaries, they usually occur in the This is the most common sexually erythropoietin—Hormone that stim- middle of the body, such as in the transmitted disease in the United ulates red blood cell production in area between the heart and lungs. States, and almost half of all cases the bone marrow. They may also develop within the are due to a chlamydial infection. brain. The prognosis for germ cell Fabry disease—A rare hereditary cancers is generally favorable, and clotting factors—Proteins involved disorder that leads to an accumula- they respond very well to in the normal clotting of blood. tion of glycolipid, a product of fat chemotherapy and radiation metabolism. The full-blown disease colony stimulating factor (CSF)— therapy. occurs only in males, who have just Protein responsible for controlling one X chromosome. glioblastoma multiforme—A rare, the production of white blood cells. fast growing, highly malignant type familial adenomatous polyposis— Crohn’s disease—A subacute of brain tumor arising from glial An inherited syndrome chronic gastrointestinal disorder, (supporting) cells within the brain. characterized by the formation of involving the small intestine, char- thousands of polyps in the colon glioma—A type of brain tumor acterized by patchy deep ulcers that and rectum with colorectal cancer arising from the supporting glial may cause fistulas and a narrowing the inevitable consequence. The cells within the brain. Gliomas and thickening of the bowel. polyps most often begin to form at make up about 60 percent of all cystic fibrosis—A genetic disorder puberty, and colon cancer usually primary brain tumors and are of the exocrine glands causing occurs 10 to 15 years thereafter. frequently malignant. abnormal mucous secretions that gastroesophageal reflux disease graft-versus-host disease (GVHD)— obstruct glands and ducts in various (GERD)—A backflow of stomach A complication in bone marrow organs, particularly the lungs. contents upward into the esophagus transplants where immune system cytokines—Naturally occurring caused by poorly functioning cells attack the transplant recipient’s proteins that regulate or modify the muscles in the lower esophagus. tissues. growth of specific cells. Because the esophagus lacks a pro- growth factors—Factors responsible tective lining, stomach acid that cytomegalovirus (CMV )—A DNA for regulating cell proliferation refluxes into it causes pain, inflam- virus related to the herpes virus, (rapid and repeated reproduction), mation (esophagitis), and damage. affecting mostly neonatal infants and function and differentiation. immunocompromised individuals. Gaucher disease—An inherited heat shock protein—A natural CMV is sexually transmitted and can disease caused by a lack or adjuvant (a substance that enhances occur without symptoms or result in deficiency of an enzyme (glucocere- the immune response to an antigen) mild flu-like symptoms. As an brosidase). Primarily affects the liver, linked to molecular signals or anti- opportunistic infection in AIDS spleen and bone marrow, usually genic peptides, which are capable patients, it can cause CMV retinitis, resulting in death. of stimulating an immune response. an inflammation of the retina that gene therapy—Therapy at the intra- The heat shock protein (HSP) core is can lead to blindness if left untreated. cellular level to replace or inactivate an invariable molecule that remains cytopenia—A below-normal number the effects of disease-causing genes the same for each patient; the anti- of blood cells. or to augment normal gene functions genic peptides are patient- and demyelinating polyneuropathy, to overcome illness. tumor-specific or pathogen-specific. chronic inflammatory—CIDP is a When purified in a certain way,

M EDICINES IN D EVELOPMENT Biotechnology 2004 39 G LOSSARY

HSP-peptide complexes constitute abnormal bleeding into the skin and leishmaniasis—Diseases affecting the “fingerprint” of the cell from from other parts of the body skin (cutaneous), mucous mem- which they were derived. When (purpura). branes and internal organs (visceral) injected into a patient, these anti- caused by a parasite called immune modulator—A substance genic peptides are re-expressed on Leishmania, which is transmitted that changes an aspect of the way the surface of important immune from infected animals or people to the immune system is working. cells—macrophages—that play a new hosts by sand flies. major role in activating the immune immunosuppression—Lowering the leukemia—Form of cancer in system, resulting in a much more body’s normal immune response to which the white blood cells grow potent immune response than the invasion by foreign substances. This abnormally. one achieved by the expression of process can be deliberate, as in low- these same peptides by the tumor ering the immune response to lipodystrophy—A disturbance in the or pathogen-infected cell. prevent rejection of a transplanted way the body produces, uses and organ, or incidental, as a side effect distributes fat. In HIV disease, it Helicobacter pylori—A bacterium of radiotherapy or chemotherapy for refers to a group of symptoms: the that grows in the mucus-secreting cancer. loss of the thin layer of fat under the cells of the stomach lining that may skin, making veins seem to protrude; cause temporary or persistent gastri- inclusion body myositis (IBM)—An wasting of the face and limbs; and tis or peptic ulcers. inflammatory muscle disease char- the accumulation of fat on the acterized by progressive muscle hemophilia A and B—Hemophilia abdomen (both under the skin and weakness and wasting. Onset of A, the “classic” hemophilia, is a within the abdominal cavity) or muscle weakness in IBM is gener- genetic bleeding disorder due to between the shoulder blades. ally gradual (over months or years). deficiency of the coagulation factor Falling and tripping are usually the lymphoma—Cancers in which the VIII. Hemophilia B, or “Christmas” first noticeable symptoms. For some cells of lymphoid tissue, found disease, is caused by deficiency of patients the disorder begins with mainly in the lymph nodes and coagulation factor IX. weakness in the hands causing diffi- spleen, multiply unchecked. hepatitis—Inflammation of the liver culty with gripping, pinching, and Lymphomas fall into two categories: with accompanying liver cell damage buttoning. IBM occurs more fre- One is called Hodgkin’s disease, or death, caused most often by viral quently in men than women and characterized by a particular kind of infection, e.g., hepatitis A, B, and C. affects both the muscles closest to abnormal cell. All others are called the center of the body and those far- non-Hodgkin’s lymphomas, which HIV—Human immunodeficiency thest from the center. Difficulty vary in their malignancy according virus (the virus that causes AIDS). swallowing (dysphagia) occurs in to the nature and activity of the human growth hormone—Pituitary about half of IBM cases. abnormal cells. hormone that stimulates the growth inflammatory bowel disease—Term MAb (monoclonal antibodies)— of long bones in prepubertal children. for inflammatory disorders affecting Large protein molecules produced human papillomavirus—Viral agent the small and/or large intestine. by white blood cells that seek out of warts, believed to be contagious and destroy harmful foreign sub- interferon—A glycoprotein naturally and mostly harmless, affecting only stances. produced by cells that interferes with the skin’s topmost layer. the ability of a virus to reproduce macular degeneration—A progres- Hunter syndrome—see after it invades the body. Interferon sive disorder that affects the central mucopolysaccharidoses. potentially might also curtail the part of the retina, causing gradual immune globulin—A class of pro- spread of certain types of cancer. loss of vision. It is a painless condition, usually affects both eyes and teins produced in lymph tissue in interleukin—An endogenous sub- is common in the elderly. vertebrates that function as antibod- stance that stimulates the production ies in the immune system’s of different types of white blood melanoma—Cancer made up of response. cells or leukocytes. pigmented skin cells. immune/idiopathic thrombocytope- ischemia—Insufficient supply of metastases/metastatic—Secondary nia purpura—A condition that may blood to an organ or tissue, which cancers that have spread from the follow a viral infection, which can can cause organ damage such as an primary or original cancer site. trigger destruction of blood platelets ischemic stroke. microbicide—A substance intended by the immune system. The reduced to significantly reduce the transmis- number of platelets may result in

40 M EDICINES IN D EVELOPMENT Biotechnology 2004 G LOSSARY sion of sexually transmitted diseases blood cells found in the bone Phase I—Safety testing and pharma- (STDs), such as HIV, chlamydia, or marrow. cological profiling in humans. the herpes virus. They may work to myocardial infarction—Damage to Phase II—Effectiveness testing in kill pathogens, block infection by the heart muscle caused by stoppage humans. pathogens by creating a barrier or impairment of blood flow to the between the pathogen and the Phase III—Extensive clinical trials in heart, also known as heart attack. reproductive tract, or prevent a virus humans. necrotizing fasciitis—An extremely such as HIV or herpes from replicat- photosensitizer—A drug used in severe form of cellulitis (bacterial ing once it enters the body. photodynamic therapy. When skin infection) that destroys infected Microbicides are not yet available absorbed by cancer cells and tissue under the skin. Some refer to on the market, but many are under exposed to light, the drug becomes it as the “flesh-eating disease.” development. They are likely to be active and kills the cancer cells. produced in the form of a gel, foam, neuroblastoma—A tumor of the Pompe disease—The most severe cream, sponge, suppository or film adrenal glands or sympathetic form of the glycogen storage dis- to be applied either in the vagina or nervous system (the part of the eases, which are a related group of rectum. nervous system responsible for rare autosomal recessive inherited certain automatic body functions, mucopolysaccharidoses— disorders in which muscles can’t such as the “fight or flight Hereditary disorders that result in a metabolize sugars normally, so they response”). Neuroblastomas are the characteristic facial appearance and build up large stores of glycogen (a most common extracranial (outside abnormalities of the bones, eyes, starch). In Pompe’s disease, glycogen the skull) solid tumor of childhood. liver, and spleen, sometimes accumulates in the liver, muscles, accompanied by mental retarda- neutropenia—An abnormally low nerves and heart, preventing them tion. The cause of these disorders neutrophil count (certain white from functioning properly. It cannot is an inability to break down and blood cells). be cured, and most infants die by store mucopolysaccharides, which age two. are major components of connective oncolytic viruses—The use of tissue. Hunter syndrome is one of viruses to preferentially infect and Prader-Willi syndrome—A genetic these disorders. kill cancer cells while not harming disorder characterized by short healthy cells. Oncolytic refers to stature, mental retardation, abnor- multiple myeloma—A malignant lysis or breakdown of cancer cells mally small hands and feet, condition characterized by uncon- through the process of apoptosis. hypogonadism, and uncontrolled trolled proliferation of plasma cells There are many methods of oncolytic appetite leading to extreme obesity. (a class of white blood cells) in bone virus therapy, all of which involve prodrug—A precursor (forerunner) marrow. Symptoms include pain and the virus becoming active in cancer of a drug. A prodrug must undergo destruction of bone tissue, numbness cells that have specific genetic and chemical conversion by metabolic and paralysis, kidney damage, metabolic transformations. anemia, and frequent infections. The processes before becoming an condition is rare and affects those of osteomyelitis—Infection of bone active pharmacological agent. For middle to older age groups. and bone marrow, usually caused example, sulfasalazine is a prodrug. by bacteria. It is not active in its ingested form. It multiple sclerosis—Progressive has to be broken down by bacteria Parkinson’s disease—Chronic neu- disease of the central nervous system in the colon into two products--5- rologic disease of unknown cause, in which scattered patches of the aminosalicylic acid and characterized by tremors, rigidity covering of nerve fibers (myelin) sulfapyridine—before becoming and an abnormal gait. Some patients in the brain and spinal cord are active as a drug. destroyed. Symptoms range from with advanced disease develop numbness and tingling to paralysis dementia. It is a common chronic prophylaxis—Preventive treatment and incontinence. disease of later life. intended to preserve health and prevent the development of disease. myeloid—(Also called myeloge- peptide—A compound containing nous.) Pertaining to, derived from, two or more amino acids. pulmonary embolism (embolus)— Obstruction of the pulmonary artery or manifesting certain features of the peripheral vascular disease—The (the blood vessel that carries blood bone marrow. In some cases, obstruction of blood supply to the from the heart to the lungs) or one myeloid also pertains to certain extremities, particularly the legs, of its branches in the lung by an types of non-lymphocyte white caused by atherosclerosis.

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embolus, usually a portion of a scleroderma—A chronic autoim- taxane—A drug that inhibits cell blood clot that originated in a vein mune disease characterized by growth by stopping cell division. in the leg or pelvis, that breaks off degenerative changes and scarring in Taxanes, such as docetaxel and and travels in the circulation to the the skin, joints, and internal organs paclitaxel, are used as treatments for lung. It can be life-threatening. and by blood vessel abnormalities. cancer. pulmonary fibrosis, idiopathic— secretagogue—A substance that thrombocytopenia—A reduction in Scarring and thickening of lung induces secretion from cells, origi- the number of platelet cells in the tissue of unknown cause. nally applied to peptides inducing blood, which causes a tendency to gastric and pancreatic secretion. bleed, especially from the smaller radioimmunotherapy—Treatment blood vessels. with a radioactive substance that is sepsis—A condition associated with linked to an antibody that will a serious bacterial infection of the thrombolytic—A kind of pharma- attach to a tumor when injected into blood. ceutical that can break up clots the body. blocking the flow of blood to the seropositive—Positive blood test for heart muscle. recombinant DNA—DNA produced evidence of an infectious disease, by joining pieces of DNA from dif- such as HIV infection. tissue plasminogen activator (t-PA) ferent sources. Usually designated —TPA is a substance produced in short bowel syndrome—The malab- as rDNA. small amounts by the inner lining of sorptive condition that arises after blood vessels that prevents abnor- recombinant soluble receptors— significant segments of the small mal blood clotting by converting Synthetic versions of cellular intestine are removed. Some of the plasminogen—a chemical in the receptors manufactured with most common causes in adults are blood—to the enzyme plasmin. recombinant DNA technology, used Crohn’s disease, radiation enteritis as decoys to attract pathogens that and trauma. ulcerative colitis—A chronic otherwise would bind to cellular inflammation and ulceration of the Staphylococcus aureus—A common receptors and cause disease. They lining of the colon and rectum. It bacterium that is a frequent cause of are “soluble” because they are free- causes bloody diarrhea and mainly hospital infections, including standing and not attached to involves the left colon. pneumonia, surgical wounds and (insoluble) cells. systemic blood infections. uveitis—Inflammation of the uvea, respiratory syncytial virus disease— the middle layer of the eye. systemic lupus erythematosus One of the most important causes of (SLE)—The most serious form of VEGF—Vascular endothelial growth lower respiratory tract disease in lupus, a chronic autoimmune factor that is responsible for the children, accounting for more than disorder causing inflammation and growth of blood vessels. 90 percent of cases of bronchiolitis. damage to multiple organs. SLE xeroderma pigmentosa—A rare, restenosis—A condition where an affects many systems of the body, inherited skin disease caused by artery plugs up again following including the joints, kidneys and extreme sensitivity to sunlight. treatment to open it up. brain. rotavirus—A virus that is a common cause of stomach upsets and diarrhea in infants.

42 M EDICINES IN D EVELOPMENT Biotechnology 2004 T HE D RUG D ISCOVERY, DEVELOPMENT AND A PPROVAL P ROCESS It takes 10-15 years on average for an experimental drug to travel from the lab to U.S. patients. Only ﬁve in 5,000 compounds that enter preclinical testing make it to human testing. One of these ﬁve tested in people is approved.

Clinical Trials Discovery/ Phase Phase Phase Phase Preclinical Testing I II III FDA IV

Years 6.5 1.5 2 3.5 1.5

20 to 100 100 to 500 1,000 to 5,000 Test Laboratory and healthy patient patient Population animal studies volunteers volunteers volunteers Review Additional process/ post- Assess safety, Determine Evaluate Conﬁrm effectiveness, approval marketing Purpose biological safety effectiveness, monitor adverse testing activity and and look for reactions from required File IND at FDA formulations dosage side effects long-term use File NDA at FDA by FDA

Success 5,000 5 1 Rate compounds evaluated enter trials approved

T HE D RUG D EVELOPMENT AND A PPROVAL P ROCESS

he U.S. system of new drug approvals is perhaps Clinical Trials, Phase I. These tests involve about Tthe most rigorous in the world. 20 to 100 normal, healthy volunteers. The tests study a It takes 10 to 15 years on average for an experimental drug’s safety profile, including the safe dosage range. drug to travel from lab to U.S. patients, according to The studies also determine how a drug is absorbed, the Tufts Center for the Study of Drug Development, distributed, metabolized, and excreted as well as the based on drugs approved from 1994 through 1998. duration of its action. Only five in 5,000 compounds that enter preclinical Clinical Trials, Phase II. In this phase, controlled testing make it to human testing. And only one of those trials of approximately 100 to 500 volunteer patients five is approved for sale. (people with the disease) assess a drug’s effectiveness. On average, it costs a company $802 million to Clinical Trials, Phase III. This phase usually involves get one new medicine from the laboratory to U.S. 1,000 to 5,000 patients in clinics and hospitals. patients, according to a November 2001 report by the Physicians monitor patients closely to confirm efficacy Tufts Center for the Study of Drug Development. and identify adverse events. Once a new compound has been identified in the New Drug Application (NDA). Following the laboratory, medicines are developed as follows: completion of all three phases of clinical trials, a Preclinical Testing. A pharmaceutical company con- company analyzes all of the data and files an NDA ducts laboratory and animal studies to show biological with FDA if the data successfully demonstrate both activity of the compound against the targeted disease, safety and effectiveness. The NDA contains all of and the compound is evaluated for safety. the scientific information that the company has gathered. NDAs typically run 100,000 pages or Investigational New Drug Application (IND). After more. The average NDA review time for 21 new completing preclinical testing, a company files an IND molecular entities (NMEs) approved by the FDA in with the U.S. Food and Drug Administration (FDA) to 2003 was 16.9 months. begin to test the drug in people. The IND becomes effective if FDA does not disapprove it within 30 days. Approval. Once FDA approves an NDA, the new The IND shows results of previous experiments; how, medicine becomes available for physicians to where and by whom the new studies will be prescribe. A company must continue to submit conducted; the chemical structure of the compound; periodic reports to FDA, including any cases of how it is thought to work in the body; any toxic adverse reactions and appropriate quality-control effects found in the animal studies; and how the records. For some medicines, FDA requires additional compound is manufactured. All clinical trials must be trials (Phase IV) to evaluate long-term effects. reviewed and approved by the Institutional Review Discovering and developing safe and effective new Board (IRB) where the trials will be conducted. medicines is a long, difficult, and expensive process. Progress reports on clinical trials must be submitted at PhRMA member companies invested an estimated least annually to FDA and the IRB. $33.2 billion in research and development in 2003.

M EDICINES IN D EVELOPMENT Biotechnology 2004 43 Genomics, Proteomics and Biotechnology— What’s in it for Patients? he complete set of genes of an organism is called its genome and is made up of DNA, or deoxyri- B IOTECHNOLOGY M EDICINES IN D EVELOPMENT—BY P RODUCT C ATEGORY T bonucleic acid. Since 1990, scientists—both in the government and in private industry—have been Angiogenesis Inhibitors 4 working together to “map” the human genome. Antisense 14 Cellular Therapy 11 DNA is found tightly coiled in every nucleus of a per- Colony Stimulating Factors 2 Enzyme Replacement Therapy 5 son’s many trillion cells. These slender threads of DNA Gene Therapy 23 have four different chemical building blocks or bases, Growth Factors 7 abbreviated as A, T, C and G. The human genome con- Immune-based Therapy 10 Interferons 10 tains about 3 billion pairs of these bases. Genes are Interleukins 8 speciﬁc pieces of DNA. They vary in length—with the Monoclonal Antibodies 76 Recombinant Human Proteins 23 average gene consisting of about 2,000 base pairs—and Recombinant Soluble Receptors 2 they differ from one another in the order, or sequence, of Signaling 3 the base pairs. This order determines which proteins the Vaccines 90 Others 34 genes encode.

Once we know the sequence of each of the genes, diseases by both conventional and biotechnology-based we can compare that data with known sequences, medicines. This means there will be more opportunities for and work out what protein the gene produces and pharmaceutical breakthroughs and, eventually, more and what that protein does in the body. This will allow better medicines. us to understand the molecular basis of many diseases, and determine who is most likely to get which illnesses, Already many medicines are based on biotechnology, and why. Ultimately, this will enable us to develop but the study of gene sequences (genomics) and the arrays of medicines that prevent or at least slow down those proteins produced by different cells (proteomics) is allowing diseases before symptoms become debilitating, as much better understanding of what makes one person opposed to many medicines today which treat the healthy and another suffer from disease. Both genomics symptoms rather than the causes of disease. and proteomics are contributing to the development of therapeutic and preventive medicines, both biotechnological Currently, pharmaceutical researchers have about and chemical. Ultimately, we hope to be able to fix the 500 targets, or genes, to pursue for intervention with gene in the person afflicted (gene therapy) and choose the medicines. With the human genome completed, there right drug for each patient the first time (pharmacogenomics), will be many more. but in the meantime we will make many more therapies More targets and an understanding of how they are available to patients as the cumulative experience in involved in the development of human disease will allow biotechnology expands our knowledge and understanding more precise treatments and the prevention of more of the human body.

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