Sponsored Links: Prescription Drug Addiction     STRATEGIC BRIEFINGS  Breakthrough Immune Modulator Targets Have Blockbuster Potential By Lucy Sannes, Ph.D., Sannes & Associates Vicki Glaser, Contributing Editor to Pharma DD, contributed to this article. November 30, 2006 As our understanding of the intricate links between inflammation and autoimmune responses and a host of common disorders, including cardiovascular disease and diabetes, continues to expand, the therapeutic and commercial potentials for using potent immunomodulatory agents to boost or suppress these immune responses continue to grow enormously.   Immunomodulators are agents that modulate the immune system, either increasing or decreasing the immune response to a particular disease or foreign agent. Immunomodulators that suppress the immune response are particularly advantageous for treating inflammatory or autoimmune diseases, including allergic responses. In contrast, immunomodulators that enhance the immune response can be exploited to target cancer or certain infectious diseases. The large number of disease targets and patients with these conditions that could benefit from treatment with immunomodulators has generated huge interest in this field.   Immunomodulators that target tumor necrosis factor (TNF)-alpha alone had combined worldwide sales of over $8.5 billion in 2005, demonstrating the large market potential for this class of agents. Table 1 lists the TNF-alpha inhibitors currently on the market. Additional TNF inhibitors are also in development.   Several immunomodulators already on the market have clearly demonstrated the range of potential indications and the possibility of developing blockbuster products, including various interferons (see Table 1 for selected examples). Another example is Chiron’s Proleukin (aldesleukin). A recombinant form of interleukin (IL)-2 and first approved by the Food and Drug Administration (FDA) in 1992, Proleukin is currently approved for treatment of metastatic renal cell carcinoma and metastatic melanoma.   Although currently available immunomodulators are effective, there is a significant need for more effective and safer immune-based therapies.   Targeting the Immune System   The immune system is highly complex and is mediated by a large number of proteins, including cytokines (proteins secreted by immune cells that act as intracellular mediators) and their receptors. Interferons and TNF-alpha are examples of cytokines. Another broad group of cytokines is the interleukins, or ILs, many of which are produced by T cells (although other immune cells can also produce ILs). Originally, it was thought that the ILs were primarily produced by and acted on leukocytes—leading to the name “interleukins.”   Numerous other proteins have been identified that have roles in the immune system. These proteins and their cellular receptors represent a treasure trove of potential drug targets for modulating the immune system.   Novel therapies focusing on a range of different immunomodulatory targets are being developed. Many of these emerging strategies either target or consist of IL molecules. Table 2 lists examples of therapies in development that target ILs or their receptors. As demonstrated by this extensive listing, no single IL has emerged as the one to target for modulating the immune system. Instead, companies are targeting a number of different ILs.   One example of an immunomodulator that has reached late-stage development is Centocor’s CNTO 1275, which is in Phase III clinical trials for treatment of psoriasis. CNTO 1275 is a human monoclonal antibody that targets both IL-12 and IL-23. Centocor (a Johnson & Johnson company) already has two other immune-modulating agents in development or on the market for autoimmune diseases: one of these is Remicade (infliximab), a chimeric anti-TNF antibody approved by the FDA for treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis. Centocor has filed for approval of Remicade as a treatment for psoriasis. In addition, the company is developing a fully human anti-TNF antibody, CNTO 148 (golimumab), which is in Phase III trials for rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Psoriasis represents a significant market opportunity because approximately 2.1% of the U.S. population has psoriasis, including more than 4.5 million adults, according to the National Psoriasis Foundation. More than 1.5 million Americans have moderate to severe psoriasis.   Another late-stage therapy targeting an interleukin is Roche’s Actemra (tocilizumab), which is in Phase III clinical development for rheumatoid arthritis and for systemic juvenile idiopathic arthritis. Actemra is a humanized monoclonal antibody targeting the IL-6 receptor and is being jointly developed with Chugai. Rheumatoid arthritis also represents a significant market opportunity, because approximately 1% of the U.S. population (2.1 million people) has rheumatoid arthritis, according to the Arthritis Foundation. Phase III data are not yet available for either of these new agents, however, so their eventual market opportunities cannot be predicted.   The potential for new therapies for autoimmune diseases, such as Roche’s Actemra or Centocor’s CNTO 1275, to achieve significant revenues is evident from the success of the approved products listed in Table 1. However, the commercial potential of these new agents will largely depend on their ability to compete effectively against current therapies.   The market opportunity for specific agents in development will depend on the indication(s) for which they receive approval. Many of these compounds are being evaluated for treatment of debilitating conditions such as asthma, cancer, and certain autoimmune diseases. If they can demonstrate improved efficacy and/or safety compared to current therapies, many of these novel immunomodulators have the potential to achieve blockbuster status. Time will tell which, if any, of the current immune system targets will emerge as “hot” targets on which a large number of pharmaceutical and biotech companies will focus, and which modulators will prove to be most effective, safe, and well-tolerated. Table 1:  Selected FDA-Approved Interferons, Interleukins (ILs), and Tumor Necrosis Factor (TNF) Inhibitors (Note: Additional immune modulator products have been approved by the FDA.) Company (drug category in italics) Product Name Year First FDA Approved Approved Indication(s) and Further Description Worldwide Sales -- 2005  ($ millions) Interferon alfa         Roche Roferon A (interferon alfa-2a) 1984 Chronic hepatitis C, hairy cell leukemia, and chronic myelogenous leukemia (CML) --- Roche Pegasys (peginterferon alfa-2a) 2002 Chronic hepatitis B and chronic hepatitis C infections Approx. $1,100 (1.403 billion CHF) Schering-Plough Intron A (interferon alfa-2b) 1983 Chronic hepatitis C, chronic hepatitis B, hairy cell leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata, and AIDS-related Kaposi’s sarcoma $287 Schering-Plough PEG-Intron (peginterferon alfa-2b) 2001 Chronic hepatitis C $751 Interferon beta         Biogen Idec Avonex (interferon beta-1a) 1996 Relapsing forms of multiple sclerosis $1,543 Schering AG (Berlex in US) Betaseron (interferon beta-1b; marketed as Betaferon outside U.S. ) 1993 Relapsing forms of multiple sclerosis Approx. $1,100 (867 million euros) Serono (co-marketed by Pfizer in U.S. ) Rebif (interferon beta-1a) 2002 Relapsing forms of multiple sclerosis Serono: $1,270 ILs         Amgen Kineret (anakinra) 2001 Rheumatoid arthritis (human interleukin-1 receptor (IL-1Ra) antagonist) --- Chiron (Acquired by Novartis in 2006) Proleukin (aldesleukin) 1992 Metastatic renal cell carcinoma and metastatic melanoma (recombinant form of IL-2) $123.5 Wyeth Neumega (oprelvekin) 1997 Prevention of severe thrombocytopenia and reduction of the need for platelet transfusions after myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia (recombinant IL-11) --- TNF Inhibitors         Amgen (marketed by Wyeth outside North America ) Enbrel (etanercept)   1998 Rheumatoid arthritis, active polyarticular-course juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis Amgen: $2,573 ( North America )   Wyeth: $1,084 (Outside North America ) Abbott Laboratories Humira (adalimumab) 2002 Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis $1,400 Centocor (Johnson & Johnson; marketed by Schering-Plough outside U.S. except in Japan and parts of the Far East ) Remicade (infliximab) 1998 Rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, and ulcerative colitis Centocor: $2,535 ($2,065 from U.S. )   Schering-Plough: $942 (international) Others         Bristol-Myers Squibb Orencia (abatacept) 2005 (launched 2/06 in U.S. ) Rheumatoid arthritis (soluble fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human immunoglobulin G1) $0, 2005; $23 million for first half of 2006 Source: Sannes & Associates, Inc.   Table 2: Selected Companies Developing Immunomodulators (Note: This table does not include interferon products that are on the market or all interferon products in development. In addition, only selected late-stage (Phase II or Phase III) agents are included that focus on other targets besides tumor necrosis factor (TNF) inhibitors, interleukins (ILs), or IL receptors. Additional immunomodulators are also being developed.) Company (drug category in italics) Product/Technology Status Comments TNF Inhibitors       AstraZeneca and Protherics CytoFab Phase II   Phase III planned •Phase II trial for sepsis. •Anti-TNF-alpha polyclonal antibody fragment (Fab). •12/05: AstraZeneca and Protherics announced a development and licensing agreement for CytoFab for treatment of sepsis. This agent was originally developed by Protherics. AstraZeneca will be responsible for development of CytoFab. Potential value of this agreement, excluding royalties, is £195 million, including an initial payment of £16.3 million. Centocor (Johnson & Johnson)   Will be marketed by Schering-Plough internationally golimumab (CNTO 148) Phase III •Being developed for treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. •Fully human monoclonal antibody targeted against human TNF-alpha. UCB (Formerly Celltech) CIMZIA (certolizumab pegol) (CDP870) Filed for FDA approval; filed for approval in Europe •Filed for approval for treatment of Crohn’s disease. •In Phase III trials for treatment of rheumatoid arthritis and in Phase II for psoriasis. •Pegylated Fab' fragment of a humanized anti-TNF-alpha monoclonal antibody. Targeting Interleukins and Interleukin Receptors Abbott Laboratories ABT-874 Phase II •Fully human monoclonal antibody that targets and neutralizes IL-12. •Being evaluated for treatment of multiple sclerosis and psoriasis. Amgen AMG 108 Phase II •Monoclonal antibody that blocks IL-1 activity. •In Phase II for rheumatoid arthritis. Amgen AMG 317 Phase I •Monoclonal antibody that blocks IL-4 and IL-13 activity. •Being developed for treatment of asthma. Amgen and Genmab AMG 714 Preclinical •Human monoclonal antibody directed against IL-15. •In preclinical development for psoriasis. Cel-Sci Multikine Has approval to start Canadian arm of a planned global Phase III trial •A combination of natural human IL-2 and certain cytokines and lymphokines. •Planned Phase III trial is for head and neck cancer. Centocor (Johnson & Johnson) CNTO 1275 Phase II/III •Human monoclonal antibody that targets IL-12 and IL-23. •In Phase II for psoriatic arthritis and Phase III for psoriasis. Neopharm cintrekedin besudotox (IL13-PE38QQR) Phase III •A recombinant protein consisting of IL-13 and the cytotoxic agent PE38. IL13-PE38QQR targets IL-13 receptors on cancer cells. Following binding of IL13-PE38QQR to the cell, it is absorbed into the cell, causing cell death. •Note: In this therapeutic approach, the IL molecule is used as a tumor-targeting agent and not as an immunomodulator. Novartis (Acquired Chiron) Proleukin (aldesleukin) On the market