Immunotherapies and Vaccines for Nontraditional Indications

Immunotherapies and Vaccines for Nontraditional Indications

Executive Summary

The earliest immunotherapies were vaccines that stimulate the immune system’s response against infectious agents, providing protection against those diseases. Vaccines and immune globulin preparations (passive immunotherapies) have been used for many years to enhance the immune system’s response against infectious diseases. More recently, a number of monoclonal antibodies have been commercialized for treatment of cancer, and a number of active immunotherapies and vaccines that stimulate the immune response against cancer are being developed. These applications of immunotherapy focus on the benefits of the immune system when it is working correctly, and the potential beneficial therapies that may be developed by enhancing the immune response.

In contrast, sometimes a person’s immune system goes awry, either attacking the person’s own body, or overreacting or producing exaggerated response to a foreign substance that is normally harmless to most people. In these situations, therapies are needed to suppress or modulate the unwanted immune response. Therapies that suppress or modulate the immune response are currently available. More are being developed for treatment of autoimmune diseases, treatment of allergies, or prevention of transplant rejection.

These are the most well-known applications of immunotherapies and vaccines that enhance the immune system. However, many other applications are possible. Research and development of immunotherapies for these other indications has been progressing for many years, even though this effort has not received the public attention that the work on infectious disease and cancer immunotherapies and vaccines has seen. This report discusses many of these other applications of monoclonal antibodies, therapies derived from antibodies, vaccines, and therapies that modulate the immune response for treatment of a wide range of disorders and diseases.

Some of the emerging therapies discussed in this report have been developed for treatment of diseases that are caused by the immune system including inflammatory diseases (diseases resulting from the immune response) and also disorders resulting from changes in the complement system. However, there are also other disorders included in this report that are not immune-mediated diseases or the result of the immune response. For these disorders, antibodies are being used as tools to block targeted proteins that have a role in the disease process. These antibodies may be delivered passively, or they may be generated by the patient’s own body in response to a vaccine.

Chapter 2 discusses the progress in developing immunotherapies and vaccines for treatment of Alzheimer’s disease. Several immunotherapies that target beta amyloid are in development, including both monoclonal antibodies and vaccines. The most advanced is bapineuzumab, which is in Phase III development by Wyeth and Elan. In this chapter, the pathophysiology, epidemiology, and current therapy of Alzheimer’s disease are discussed. This is followed by a section that discusses why companies are developing antibodies and vaccines for treatment of Alzheimer’s disease. The next section of Chapter 2 discusses many of the emerging immunotherapies for Alzheimer’s disease that have reached clinical development. Even more emerging immunotherapies for this indication are included in a table that accompanies this section. The final section of this chapter discusses business considerations for companies that are developing immunotherapies for treatment of Alzheimer’s disease.

Similar sections are included in each of the subsequent chapters about different disease indications. Chapter 3 discusses immunotherapies that are being developed for treatment of two different addictions: nicotine and cocaine. With these immunotherapies, antibodies are either passively administered or are produced by the patient’s body in response to a vaccine. The antibodies then bind to either nicotine or cocaine, creating a large molecule that cannot be transported across the bloodbrain barrier. Immunotherapies are being developed for a wide range of different neurological indications, and several of these additional indications are discussed in Chapter 4 and/or are included in a table of therapies in development that accompanies Chapter 4. These additional neurological conditions include pain, multifocal motor neuropathy, treatment of pain in dental patients undergoing third-molar extraction, treatment of ankylosing spondylitis, rheumatoid arthritis, chronic low back pain, endometriosis, the pain associated with cancer that has metastasized to the bone, blocking a protein that inhibits axonal regeneration (for treatment of stroke), and Parkinson’s disease.


Immunotherapies (including antibodies and vaccines) are also being developed for treatment of different cardiovascular disorders. These are discussed in Chapter 5. The targeted cardiovascular disorders include angina, atherosclerosis, dyslipidemia, hypertension, venous thromboembolism, and digoxin toxicity. Chapter 6 discusses the development and use of immunotherapies for hematological disorders including idiopathic (immune) thrombocytopenic purpura (ITP), paroxysmal nocturnal hemoglobinuria (PNH), and Rh incompatibility and hemolytic disease of the newborn (HDN).

Antibodies can also be used for treatment of ophthalmic diseases. As discussed in Chapter 7, Lucentis (ranibizumab) is an antibody fragment that binds to and inhibits VEGF. It is FDA approved for treatment of neovascular (wet) age-related macular degeneration. It is also in late-stage clinical development for additional ophthalmic indications. A human monoclonal antibody against VEGF, Genentech’s/Roche’s Avastin (bevacizumab), is FDA approved for treatment of colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. While Avastin is not approved for treatment of wet AMD, it is also used for this indication. Other examples of ophthalmic diseases for which antibodies are being developed include diabetic retinopathy and diabetic macular edema, retinal vein occlusion, and uveitis. Chapter 8 discusses the development of antibodies for treatment of osteoporosis and other bone metabolism disorders. The most advanced of these is Amgen’s denosumab, which is a human monoclonal antibody that targets the receptor activator of nuclear factor kappa beta ligand (RANKL). Denosumab has been submitted to the FDA. Ablynx (Belgium) is developing nanobodies that target RANKL. These are in preclinical development. In addition, Amgen (with UCB Pharma) is also developing Sclerostin Ab, a humanized antibody that targets the protein sclerostin.

In addition, multiple monoclonal antibodies are being developed for treatment of type 2 diabetes. Three companies are developing antibodies that target IL-1 beta, a pro-inflammatory cytokine that stimulates the immune response. The second molecule being targeted by a monoclonal antibody in development for type 2 diabetes is the glucagon receptor. These are discussed in Chapter 9. In addition to all of these activities in neurology, cardiovascular disease, hematology, ophthalmology, osteoporosis, and type 2 diabetes, many additional antibodies, antibody-based drugs, and other immunotherapies/anti-inflammatory drugs are being developed to treat a wide range of indications. Several examples of those that have reached clinical development are discussed in Chapter 10, and even more are included in the table that accompanies Chapter 10. This report also includes seven interviews with experts in the application of antibodies, antibody-derived therapies, and vaccines to the treatment of various diseases included in this study. These experts discuss the progress, challenges, and hurdles faced by researchers and companies working in this field.

Table of Contents

1.1.The Immune Syste
1.2. Scope of the Report

Chapter 2 - ALZHEIMER’S DISEASE

2.1. Alzheimer’s Disease Pathophysiology, Epidemiology, and Current Treatments
2.2. Why Immunotherapies or Vaccines for Treatment of Alzheimer’s Disease?
2.3. Companies Developing Immunotherapies or Vaccines for Alzheimer’s Disease
AFFiRiS
Baxter
Novartis and Cytos Biotechnology
Eli Lilly
Genentech and AC Immune
GlaxoSmithKline
Merck & Co.
Octapharma
Pfizer
Roche and MorphoSys
Wyeth and Elan
2.4. Business Considerations: Immunotherapies for Alzheimer’s Disease
Chapter 3 – ADDICTION

3.1. Pathophysiology, Epidemiology, and Current Treatments
Cocaine Addiction
Nicotine Addiction (Smoking Cessation)
3.2. Why Immunotherapies for Addiction?
3.3. Companies Developing Immunotherapies for Cocaine Addiction or Smoking Cessation
Cocaine Addiction
Celtic Pharma
Nicotine Addiction (Smoking Cessation)
Celtic Pharma
Nabi Biopharmaceuticals
Novartis and Cytos Biotechnology
3.4. Business Considerations: Immunotherapies for Cocaine Addiction or Smoking Cessation

Chapter 4 - OTHER NEUROLOGY INDICATIONS FOR MONOCLONAL ANTIBODIES AND IMMUNOTHERAPIES

4.1. Pathophysiology, Epidemiology, and Current Treatments
Multifocal Motor Neuropathy
Pain
Post-Polio Syndrome
Other Potential Neurology Indications
4.2. Why Immunotherapies for Treatment of Pain?
4.3. Companies Developing or Marketing Immunotherapies for Other Neurological Indications
Alexion Pharmaceuticals’ Soliris (eculizumab)
Array BioPharma’s ARRY-797
Baxter’s Immune Globulin
CSL Behring’s Immune Globulin
GlaxoSmithKline’s 249320 (GSK249320)
Pfizer’s Tanezumab
Pharmalink’s Xepol (XP-28)
Talecris Biotherapeutics’ Gamunex
4.4. Business Considerations: Immunotherapies for Other Neurological Indications

Chapter 5 - CARDIOVASCULAR DISEASES INCLUDING THROMBOSIS


5.1. Pathophysiology, Epidemiology, and Current Treatments
Angina
Atherosclerosis
Dyslipidemia (Elevated Cholesterol and Other Lipids)
Hypertension
Venous Thromboembolism
Digoxin Toxicity
5.2. Why Immunotherapies for Selected Cardiovascular Diseases?
5.3. Companies Developing Immunotherapies for Cardiovascular Diseases
Ablynx’ ALX-0081 and ALX-0681
BTG’s DigiFab
BTG’s Angiotensin Therapeutic Vaccine
Centocor Ortho Biotech’s and Eli Lilly’s ReoPro (abciximab)
Cytos Biotechnology’s CYT006-AngQb
Genentech’s and BioInvent International’s BI-204 (anti-oxLDL)
GlaxoSmithKline’s Digibind
Roche’s and Genmab’s R1512
ThromboGenics’ and BioInvent International’s TB-402
5.4. Business Considerations: Immunotherapies for Cardiovascular Diseases

Chapter 6 - HEMATOLOGY/BLOOD DISORDERS

6.1. Pathophysiology, Epidemiology, and Current Treatments
Idiopathic (Immune) Thrombocytopenic Purpura (ITP)
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Rh Incompatibility and Hemolytic Disease of the Newborn (HDN)
6.2. Why Immunotherapies for Selected Hematology/Blood Disorders?
6.3. Companies Developing or Marketing Immunotherapies for Hematology/Blood Disorders
Alexion Pharmaceuticals’ Soliris (eculizumab)
Amgen’s Nplate (romiplostim)
Immune Globulin Preparations for Idiopathic (Immune) Thrombocytopenic Purpura (ITP)
Rho(D) Immune Globulin Preparations and LFB’s Anti-Rhesus D Monoclonal Antibody
6.4. Business Considerations: Immunotherapies for Hematology/Blood Disorders

Chapter 7 – OPHTHALMOLOGY

7.1. Pathophysiology, Epidemiology, and Current Treatments
Age-Related Macular Degeneration (AMD)
Diabetic Retinopathy and Diabetic Macular Edema
Retinal Vein Occlusion
Uveitis
7.2. Why Antibody-Based Therapies for Selected Ophthalmic Diseases?
7.3. Companies Developing Antibody-Based Therapies for Ophthalmic Diseases
ESBATech’s ESBA105
Genentech’s and Novartis’ Lucentis (ranibizumab)
Lpath’s iSONEP (sonepcizumab)
7.4. Business Considerations: Antibody-Based Therapies for Ophthalmic Diseases

Chapter 8 - OSTEOPOROSIS AND OTHER BONE METABOLISM DISORDERS


8.1. Pathophysiology, Epidemiology, and Current Treatments
8.2. Why Antibodies for Selected Bone Metabolism Disorders?
8.3. Companies Developing Antibodies for Osteoporosis and Other Bone Metabolism Disorders
Ablynx’ ALX-0141
Amgen’s Denosumab
Amgen’s and UCB Pharma’s Sclerostin Ab
8.4. Business Considerations: Antibodies for Osteoporosis and Other Bone Metabolism Disorders

Chapter 9 - TYPE 2 DIABETES

9.1. Pathophysiology, Epidemiology, and Current Treatments
9.2. Why Monoclonal Antibodies for Type 2 Diabetes?
9.3. Companies Developing Monoclonal Antibodies for Type 2 Diabetes
Amgen’s AMG 477
Cytos Biotechnology’s CYT013-IL1bQb
Novartis’ Ilaris (canakinumab)
Xoma’s XOMA 052
9.4. Business Considerations: Monoclonal Antibodies for Type 2 Diabetes

Chapter 10 - OTHER APPLICATIONS OF ANTIBODIES AND IMMUNOTHERAPIES


10.1. Companies Developing Antibodies, Antibody-Based Drugs, and Anti-inflammatory Drugs for Other Indications
Amgen’s AMG 745
AstraZeneca’s and BTG’s CytoFab
BTG’s CroFab and ViperaTAb
ESBATech’s ESBA105
FibroGen’s FG-3019
Genzyme’s GC1008
GlaxoSmithKline’s 656933 (Sb656933)
Novartis’ Ilaris (canakinumab)
Immune Globulin Preparations for Other Indications
10.2. Business Considerations: Antibodies and Immunotherapies for Other Indications

Chapter 11 - EXPERT INTERVIEWS

11.1. Steven Glazer, MD; Senior Vice President, Development; BioInvent International
11.2. Josefin-Beate (Josi) Holz, MD, Chief Medical Officer & Eva-Lotta Allan, Chief Business Officer; Ablynx
11.3. David Y. Liu, PhD, Vice President, Research & William Hodder, Vice President, Business Development; FibroGen
11.4. Steve Pakola, MD; Chief Medical Officer; ThromboGenics
11.5. Andrea Pfeifer, PhD; Chief Executive Officer; AC Immune
11.6. Roger Sabbadini, PhD; Founder, Vice President, Chief Scientific Officer; Lpath
11.7. Walter Schmidt, PhD; Chief Executive Officer; AFFiRiS
References

Tables and Figures

FDA-Approved Drugs for Treatment of Alzheimer's Disease
Selected Companies Developing Immunotherapies (Monoclonal Antibodies or Vaccines) for Treatment of Alzheimer's Disease
FDA-Approved Drugs for Use as an Aid in Smoking Cessation
Selected Companies Developing Vaccines for Treatment of Cocaine Addiction or Nicotine Addiction (Smoking Cessation)
Selected Non-Opioid Analgesics
Selected Opioid Analgesics
Selected Companies Developing and/or Marketing Immunotherapies (Antibodies, Antibody-Derived Agents, or Vaccines) for Other Neurology Applications
Selected Heart/Cardiovascular Drugs Including Lipid-Lowering Drugs and Drugs for Treatment of Hypertension
Selected Companies Developing and/or Marketing Immunotherapies (Antibodies, Antibody-Derived Agents, or Vaccines) for Cardiovascular Diseases
FDA-Approved Immune Globulin Intravenous (IGIV) Preparations and Their Indications
FDA-Approved Rho(D) Immune Globulin and Immune Globulin Intravenous Preparations
Current Non-Immune Globulin Therapies for Selected Hematology Indications
Emerging Immunotherapies for Treatment of Hematology/Blood Disorders
Current Pharmacological Therapies for Wet Age-Related Macular Degeneration
Emerging Antibody-Based Therapies for Ophthalmic Diseases
FDA-Approved Drugs for Prevention and Treatment of Osteoporosis
Emerging Antibodies and Antibody-Derived Therapies for Osteoporosis and Other Bone Metabolism Disorders
FDA-Approved Drugs for Treatment of Type 2 Diabetes
Emerging Monoclonal Antibodies for Treatment of Type 2 Diabetes
Emerging Antibodies, Antibody-Based Drugs, and Anti-inflammatory Drugs for Selected Other Indications