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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 (melanoma and renal cell carcinoma) Phase II [Non-Hodgkins lymphoma (NHL); in combination with rituximab]	•Human recombinant IL-2
Protox Therapeutics ( Canada )	PRX321	Phase II	•A protein that consists of IL-4 combined with Pseudomonas exotoxin. PRX321 binds to IL-4 receptors, which are highly expressed in a number of different types of cancers. PRX321 is then internalized by the cancer cell, and the toxin causes cell death. •In Phase II for brain cancer (glioblastoma multiforme and malignant astrocytoma); In Phase I for solid cancers and in preclinicals for other cancers. •Note: In this therapeutic approach, the IL molecule is used as a tumor-targeting agent, and not as an immunomodulator.
PDL BioPharma (Formerly Protein Design Labs)	Daclizumab	Phase II (multiple sclerosis) On the market (prevention of renal allograft rejection)	•Humanized monoclonal antibody targeted to the alpha chain (CD25) of the IL-2 receptor on activated T cells. •In Phase II trial in patients with multiple sclerosis. •Phase II trials planned in patients with asthma and in patients requiring renal transplant as possible maintenance therapy to prevent rejection. •Marketed by Roche under the trade name Zenapax for prevention (prophylaxis) of acute renal allograft rejection. •Protein Design Labs has exclusive worldwide rights for Zenapax for all disease indications other than organ transplantation.
Regeneron	IL-1 Trap	Phase III	•Designed to bind to and neutralize IL-1. •In clinical trials for certain inflammatory diseases. •In Phase III for improvement of chronic inflammation in patients with CIAS1-Associated Periodic Syndromes (CAPS).
Renovo	Prevascar (human recombinant IL-10)	Phase II	•In Phase II trial for prevention and reduction of scarring of the skin •In preclinical development for prevention and reduction of scarring after corneal injury, and is being evaluated in scarring after peripheral nerve injury.
Riken ( Japan )	--	Research	•6/06 announcement and publication of a study in which the researchers found that production of IL-4 is controlled by a memory T-cell that transmits a signal called Notch. The authors note that IL-4 plays a role in allergic reactions. •Research was performed as part of a collaboration between the Research Center for Allergy and Immunology at Riken Yokohama Institute and Kyoto University .
Roche	Actemra (tocilizumab)	Phase III	•Humanized anti-IL-6 receptor monoclonal antibody. •In Phase III for rheumatoid arthritis and for systemic juvenile idiopathic arthritis. •Being developed by Roche and Chugai. •Projected filing in 2007.
Sirna Therapeutics	--	Preclinical	•Sirna is developing short-interfering RNA (siRNA) molecules to prevent gene expression of targeted molecules. •In preclinical development for respiratory diseases (including asthma, COPD, and others), Sirna is targeting IL-4R (interleukin-4 receptor). •Corporate partner for respiratory diseases is GlaxoSmithKline.
Synta Pharmaceuticals	apilimod mesylate (STA-5326)	Phase II	•Oral IL-12/IL-23 inhibitor. •In Phase II trials for rheumatoid arthritis and common variable immunodeficiency (CVID).
Vical	IL-2/EP	Phase I	•For metastatic melanoma. •Gene therapy procedure that involves direct injection of pDNA encoding IL-2 after electroporation. The tumor cells then produce high levels of IL-2.
ZymoGenetics	IL-21	Phase I	•Immunotherapeutic agent in Phase I for treatment of metastatic renal cell carcinoma, metastatic melanoma, and (in combination with Rituxan) NHL.
ZymoGenetics	IL-29 (also known as interferon lambda-1)	Preclinical	•For treatment of hepatitis C.
Selected Other Targets (Phase II or Phase III)
Amgen	denosumab (Formerly called AMG 162)	Phase II (Rheumatoid arthritis)	•Human monoclonal antibody that targets the receptor activity of nuclear factor B ligand (RANKL). •In Phase III for bone loss induced by hormone ablation therapy for breast or prostate cancer. In Phase II for bone metastases in breast cancer, for prolonging bone metastases-free survival, and for postmenopausal osteoporosis.
AstraZeneca	AZD9056	Phase II	•Ion-channel blocker. •In Phase II for rheumatoid arthritis, inflammatory bowel disease, and COPD.
Biogen Idec	BG-12 (Oral fumarate)	Phase III ( Germany )	•Has an immunomodulatory mechanism of action. •In Phase III trial for treatment of psoriasis. •Also being evaluated for other diseases including multiple sclerosis (in Phase II). •Originally developed by Fumapharm AG ( Switzerland ), and licensed to Biogen Idec.
Coley Pharmaceutical and Pfizer	CPG 7909 (PF-3512676) (ProMuneT)	Phase III	•Coley is developing toll-like receptor (TLR) therapeutics, which are synthetic nucleic acids that are agonists or antagonists of TLRs in immune cells. Current focus is on TLR9. •CPG 7909 is in Phase III for NSCLC (with chemotherapy). It has also been evaluated in many other cancers including melanoma, renal cell carcinoma, NHL, cutaneous T-cell lymphoma (CTCL), and basal cell carcinoma. •Development and worldwide marketing rights have been granted to Pfizer.
Human Genome Sciences and GlaxoSmithKline	LymphoStat-B (belimumab)	Phase III start planned for systemic lupus erythematosus (SLE)	•Human monoclonal antibody that inhibits B-lymphocyte stimulator (BlyS). •Potential therapy for SLE and other autoimmune diseases, including rheumatoid arthritis.
Human Genome Sciences and Novartis	Albuferon (albumin-interferon alpha)	Phase III planned to start by end of 2006	•Novel long-acting form of interferon alpha that is created by fusing the gene for human albumin to the gene for interferon alpha 2b.
InterMune	Interferon Gamma-1b	Phase III	•Bioengineered interferon gamma (a natural biological response modifier) with multiple effects including immunomodulatory, antiviral, and others. •In Phase III for treatment of idiopathic pulmonary fibrosis.
InterMune	pirfenidone	Phase III	•Orally active small molecule with multiple activities that reportedly may include down-regulation of production of multiple cytokines, blocking of proliferation and stimulation of fibroblasts in response to cytokines, and inhibition of collagen synthesis. •In Phase III for treatment of idiopathic pulmonary fibrosis.
Lorus Therapeutics ( Canada )	Virulizin	Phase III	•An immunomodulator that recruits human macrophages and monocytes and stimulates release of TNF-alpha. •Lead cancer indication is pancreatic cancer. •Phase III trial in pancreatic cancer started November 2001. Enrollment completed June 2004. Results presented February 2006. Virulizin did not reach statistical significance in overall mean survival times, but subgroup analysis results were positive. •Lorus reports that partnership discussions are ongoing based on results of the positive subgroup analysis.
Medarex and Bristol-Myers Squibb	MDX-010 (ipilimumab)	Phase III	•MDX-010 is an anti-CTLA4 antibody. Found on T cells, CTLA-4 is thought to be responsible for suppressing the immune response. MDX-010 may make it possible for the immune system to be more effective in fighting cancers such as melanoma and others.
Pfizer and Abgenix	ticilimumab (CP-675,206)	Phase III	•Monoclonal antibody targeted to CTLA-4 that enhances the immune system to attack cancer cells. •For metastatic melanoma.
PDL BioPharma (Formerly Protein Design Labs)	Visilizumab (Nuvion)	Phase II	•Humanized monoclonal antibody targeted to the CD3 antigen on the surface of T lymphocytes. •In a Phase II/III study in patients with intravenous steroid-resistant ulcerative colitis, and in Phase II in patients with Crohn’s disease.