Treatment of inflammatory disorders represents a large market opportunity that has attracted numerous companies developing agents against a wide range of novel targets. Among these new targets are chemokines, proteins that attract immune system cells to inflammation sites.  The chemokine system consists of more than 50 known ligands and approximately two dozen receptors. Most of these receptors belong to one of two major subfamilies based on the arrangement of two of the first four cysteine residues in the protein's molecule—the CXC chemokines and the CC chemokines.

Because of their functions, these proteins seem like ideal targets for the challenging field of anti-inflammatory drug development.  Although many drugs exist that address common inflammatory conditions, plenty of room for improvement in the treatment of most of these diseases remains. For one thing, the range of inflammatory conditions is huge. In addition, many of these diseases are poorly served by current drugs.  In rheumatoid arthritis, for example, many drugs can be used to control pain and improve mobility. Unfortunately, some patients do not respond to even the most effective drugs available. Moreover, some of the best drugs require injection, and serious side effects are common. Finally, better drugs to slow the actual disease process are needed urgently.

Another reason for the high level of interest in chemokine receptors is that they are G-protein coupled receptors (GPCRs), the largest known class of commercially successful molecular targets. Approximately 30% of all the drugs on the market target GPCRs, and experts estimate that GPCR-targeting drugs account for about $60 billion in annual sales. Many of these drugs are blockbusters that have raked in sales in excess of $2 billion per year.  Olanzapine  (Lilly's Zyprexa), sumatriptan succinate (GlaxoSmithKline's Imitrex), and famotidine (Merck's Pepcid) all target GPCRs. Agents directed at the chemokine system are regarded as particularly promising as potential new therapies for treatment of a wide range of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, asthma, transplant rejection, atherosclerosis, and others. 

The CCR2 chemokine receptor and its primary ligand, monocyte chemoattractant protein-1 (MCP-1), are two of the most popular members of the family under study. These two proteins play key roles in attracting monocytes to an inflammation site, where the immune cells become macrophages that secrete inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and others.

Interest in CCR2 antagonists surged in November 2005 when Pfizer and Incyte announced that they had entered into a global collaborative research and licensing agreement focused on such compounds. Pfizer received worldwide development and commercialization rights for Incyte's CCR2 antagonists for all indications except multiple sclerosis and one additional (undisclosed) indication.  Incyte also retained rights to certain compounds.  Pfizer agreed to pay Incyte an up-front payment of $40 million, milestone payments of up to $743 million, and royalties on sales.  In addition, Pfizer agreed to purchase $10 million in convertible subordinated notes and another $10 million in notes after Incyte files an investigational new drug ( IND) application for a retained Incyte indication.

The deal was an important win for Incyte, which entered the field of drug discovery as recently as November 2002. Prior to that time, the company was a genomic information seller. Interestingly, the CCR2 program was the company's first fully staffed drug development project; Incyte took just four years to net a lucrative deal with the world's largest pharmaceutical company.  It wasn't beginner's luck that got Incyte where it is today, however. The man who guided Incyte through its dramatic rebirth was CEO Paul A. Friedman, former president of DuPont Pharmaceuticals Research Laboratories and head of DuPont's anti-inflammatory program until DuPont sold its pharmaceutical division to Bristol-Myers Squibb in 2001. When Friedman joined Incyte in 2001, not only did a large number of his team members accompany him, but the group even rented out the same building in Delaware that it had occupied when working for Dupont. Within almost a year, the CCR2 program was announced.

CCR2s in Development

Incyte's most advanced CCR2 antagonist is INCB3284, which is currently in Phase IIa clinical trials in rheumatoid arthritis and obese insulin-resistant patients. Incyte reports that, in addition to INCB3284 and related compounds, it has developed additional compounds that are distinct from the INCB3284 chemical series. Incyte's focus has been on the discovery and development of orally active chemokine receptor antagonists.

At least two additional companies have CCR2 antagonists in Phase II clinical trials.  Merck's MK0812 is being evaluated in patients with relapsing-remitting multiple sclerosis.  Merck has also conducted research on the potential use of CCR2 for other indications including neuropathic pain.

Millennium Pharmaceuticals also has a CCR2 antagonist in Phase II development, but has followed a different strategy in this development program.  MLN1202 is a humanized monoclonal antibody that targets the CCR2 chemokine receptor.  It is currently being evaluated in Phase II trials for rheumatoid arthritis, multiple sclerosis, and atherosclerosis.  Additional studies, including a Phase II trial in patients with scleroderma, are planned.

Several other agents that target the CCR2/MCP-1 system are in earlier stages of development.  For example, ChemoCentryx has filed an IND application and plans to start Phase I development of CCX915, an orally available CCR2 antagonist that is also being developed for treatment of multiple sclerosis.  In addition, Telik has an MCP-1 antagonist in preclinical development for treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, asthma, and cancer. Telik has exclusive rights to this MCP-1 antagonist in North and South America, but shares commercialization rights in Europe with the Japanese pharmaceutical company Sanwa Kagaku Kenkyusho.

In addition to these development programs, researchers at several major pharmaceutical companies have published articles and/or been granted patents relating to CCR2 (or MCP-1) antagonists.  These companies include AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, and UCB.  However, it is not clear whether any of these companies is actively developing CCR2 antagonists at this time.  Before their company's agreement with Incyte, scientists at Pfizer (and its predecessor companies Warner-Lambert and Pharmacia & Upjohn) had conducted research on CCR2 and MCP-1.  Multiple patents had been issued, and several research articles published.  This prior experience in the field of CCR2 and MCP-1 antagonists may have helped fuel Pfizer's interest in Incyte's CCR2 antagonist program.

Table 1:  Selected CCR2 Antagonists in Development

 

Company	Product	Status	Comments
ChemoCentryx	CCX915	IND filed Phase I study to start by end of 2005	Orally available selective inhibitor of the CCR2 chemokine receptor CCX915 is being developed for treatment of multiple sclerosis. ChemoCentryx indicates that it is developing CCR2 antagonists for treatment of inflammatory diseases such as multiple sclerosis and atherosclerosis.
Incyte and Pfizer	INCB3284	Phase IIa	Oral CCR2 antagonist In Phase II trials for treatment of rheumatoid arthritis and type 2 diabetes 11/05:  Agreement between Incyte and Pfizer announced
Merck	MK0812	Phase II	In Phase II clinical trial for treatment of relapsing-remitting multiple sclerosis.
Merck	--	Research	Has evaluated the potential use of CCR2 antagonists for additional indications including pain.
Millennium Pharmaceuticals	MLN1202	Phase II	Humanized monoclonal antibody that targets the CCR2 chemokine receptors In Phase II trials for rheumatoid arthritis, multiple sclerosis, and atherosclerosis.
Telik	MCP-1 antagonist	Preclinicals	This agent is being studied fFor treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, asthma, and cancer. Telik has exclusive commercialization rights in North and South America, and shares commercialization rights with Sanwa in Europe.

 Source: Sannes & Associates

A Growing Number of Competitors

The immune system is highly complex, and treating immune-related diseases remains an area of intense unmet need.  In addition to the CCR2 antagonists, many other emerging drug targets have been identified for treatment of inflammation and inflammatory diseases, including Mitogen-Activated Protein (MAP) Kinase inhibitors, cell adhesion molecule antagonists, and interleukin inhibitors.

Many of these emerging targets are cytokines, which are proteins that are released by immune system and help regulate the immune response.  One of the first cytokines to be targeted was TNF-alpha.  TNF-alpha inhibitors on the market today include Abbott's Humira (adalimumab), Amgen's Enbrel (etanercept), and Centocor's Remicade (infliximab).  Although these agents have rapidly become well-established products, these and other emerging TNF-inhibitors are included in the table of emerging targets (Table 1) because considerable clinical development activities are ongoing to further expand the use of TNF-alpha inhibitors for treatment of inflammatory disorders.  Product candidates for other emerging targets have also reached at least Phase II clinical trials.  The table includes a category of "other" targets, demonstrating the wide range of targets that have reached mid- to late-stage clinical trials for inflammatory disorders.

The size of the market for novel anti-inflammatory agents has been demonstrated by the recent success of the TNF-alpha inhibitors, the most recent class of anti-inflammatory agents to reach the market, The following financial figures demonstrate the tremendous demand for these agents:

• Abbott reported Humira sales of $852 million in 2004. 
• Amgen/Wyeth reported Enbrel sales in North America of $1.9 billion in 2004.  In addition, Wyeth reported Enbrel sales outside of North America of $680 million in 2004.
• Johnson & Johnson (which owns Centocor) reported Remicade sales worldwide of $2.1 billion in 2004. 

Worldwide sales of these three products alone exceeded $5 billion in 2004, and the companies continue to work to expand the approved indications. Enbrel is already approved for several types of arthritis, as well as ankylosing spondylitis and psoriasis.

If the still very young CCR2 antagonist field is going to become a major segment of the anti-inflammatory market, these drugs will need to demonstrate equal or improved benefits over the TNF-inhibitors.  At this point, CCR2 antagonists are still being evaluated in a wide range of diseases; interesting surprises could lie ahead. Certainly, the field of immune research is rapidly advancing and the results of this research will help companies decide the best therapeutic arenas in which to pioneer these intriguing new compounds.

 References and Links

Matsumoto, AK, AK, and Bathon, J. "Rheumatoid arthritis treatments." Johns Hopkins Arthritis Center.

O'Dell , JR. "Therapeutic strategies for rheumatoid arthritis." New England Journal of Medicine. 2004 Jun(350):2591-2602.

Olsen, NJ, NJ, and Stein, M. "New drugs for rheumatoid arthritis." New England Journal of Medicine. 2004 May;350:2167-2179. 

Rhen, T, and Cidlowski, JA. "Antiinflammatory action of glucocorticoids  – new mechanisms for old drugs." New England Journal of Medicine. 2005 Oct;353:1711-1723. 

"Analgesia and anti-inflammatory drug information." Center for Drug Evaluation and Research (CDER).

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