Rheumatoid Arthritis: Emerging Drug Discovery Targets And Therapeutic Candidates

Published by: LeadDiscovery

Published: Oct. 1, 2003

Table of Contents

Summary

Introduction

Rheumatoid Arthritis and its Treatment

Drugs in Development for the Treatment of Rheumatoid Arthritis

Drugs targeting the metabolism of arachidonic acid

Cyclooxygenase (COX) Inhibitors

Table 1. Selective COX2 inhibitors

Drugs targeting other sites of arachidonic acid metabolism

Phospholipase A2 Inhibitors

Lipoxygenase Inhibitors

Variations on NSAIDs

Table 2. Drugs in development targeting arachidonate metabolism

Drugs targeting inflammatory cytokines

Biological Inhibitors of cytokines

Anti-TNF Monoclonal Antibodies

TNF receptors and binding proteins

Table 3. Biopharmaceutical approaches to neutralizing TNF

Other TNF receptor family members

RANK

Osteoprotegerin

Interleukin-1 antagonists

Other cytokine-targeted biologicals

Interleukin-6

Interleukin-8

Interleukin-10

Interleukin-12

Interleukin-15

Interleukin-18

Lymphotoxin â

B-lymphocyte stimulator

Comment

Table 4. Biopharmaceutical Products targeting IL-1 and other cytokines

New Chemical Entities (NCEs) designed to inhibit cytokines

Inhibitors of p38 mitogen activated protein kinase (MAPK)

Inhibitors of cytokine activating enzymes

Inhibitors of Phosphodiesterase type 4

Other approaches to cytokine inhibiting NCEs

Table 5. New Chemical Entities (NCEs) targeting cytokine synthesis

Drugs targeting the movement and activation of inflammatory leukocytes

Inhibitors of chemotaxis

Antagonists of the complement fraction 5a

Chemokine Antagonists

Table 6. Drugs targeted at leukocyte chemotaxis

Drugs targeting Adhesion Molecules

Selectins

Lymphocyte Function Antigen-1 (LFA-1, CD11a) antagonists

Very Late Antigen-4 (VLA-4) antagonists

Table 7. Drugs targeting adhesion molecules

Other Adhesion Molecule Targets

Drugs designed to specifically regulate lymphocyte activation

Inhibitors of lymphocyte intracellular enzymes

Macrolide immunosuppressants

Selective inhibitors of nucleotide metabolism

Table 8. Inhibitors of lymphocyte intracellular mechanisms

Drugs targeting cell surface receptors on lymphocytes

CD2

CD3

CD4

CD20

CD25

CD40 and CD40 Ligand

CD80 (B7)

CD152 (CTLA4)

Table 9. Biopharmaceuticals targeting lymphocyte cell surface molecules

Vaccines and desensitizing agents

Table 10. Vaccines and Desensitizing agents

Anti-proliferative Agents for Rheumatoid Arthritis

Table 11. New approaches to anti-proliferatives for rheumatoid arthritis

Protease Inhibitors

Matrix Metalloprotease Inhibitors

Elastase Inhibitors

Cathepsin Inhibitors

Table 12. Protease Inhibitors for Rheumatoid Arthritis

Anti-angiogenic Agents for Rheumatoid Arthritis

Table 13. Anti-Angiogenic Agents

Targets for novel anti-angiogenic molecules

Growth Factors

Cytokines

Chemokines

Matrix Metalloproteases

Plasminogen activators

Angiostatic molecules

Cell adhesion molecules

Analgesics for Rheumatoid Arthritis

Table 14. Analgesics for Arthritis

Abstract

The autoimmune diseases are receiving increasing attention in the pharmaceutical industry as progress is made in the understanding of immune and inflammatory processes. It is predicted that the annual value of the market for drugs used to treat autoimmune disease will exceed $20 billion in the next few years. Rheumatoid arthritis is one of the more common and difficult to treat autoimmune diseases and there is a great deal of interest in the discovery of novel drugs to treat this condition.

Rheumatoid arthritis is a chronic syndrome characterized by non-specific, usually symmetrical inflammation of the peripheral joints, manifested by the formation of hypertrophied synovia known as panni. Pannus formation mirrors the destruction of articular and peri-articular structures, with or without generalized manifestations. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age.

Since the birth of the modern pharmaceutical industry just over 100 years ago with the synthesis of aspirin, non-steroidal aspirin-like anti-inflammatory drugs (NSAIDs) have been the mainstay of the treatment of rheumatoid and other forms of arthritis. It is generally accepted that NSAIDs relieve the symptoms of arthritis such as pain and swelling without changing the course of underlying disease. There have been considerable efforts to develop drugs which modify disease progress and these have met with variable success. Immunosuppressants such as cyclosporine or anti-metabolite drugs such as methotrexate are effective but have dose-limiting adverse effects.

During the last few years however, basic research efforts have significantly progressed our understanding of autoimmune disorders such as rheumatoid arthritis. The disease is caused by increased chemotactic and immunostimulatory activity within the joints of sufferers resulting in an influx of inflammatory cell. The presence of activated immune cells increases local levels of cytokines and other inflammatory mediators propagating this process and supporting pannus proliferation and neovasculaturization, cartilage and bone erosion and eventual joint destruction.

Although significant efforts have resulted in the development of the COX2 inhibitors celebrex and vioxx, one of the most exciting developments in the management of rheumatoid arthritis has been the introduction of the anti-TNF biopharmaceuticals remicade and enbrel. These drugs represent a real step forward in the development of anti-inflammatory therapies. There is now an increasing number of inflammatory cytokines which have become targets for therapeutic intervention with biologicals such as monoclonal antibodies or immuno-fusion proteins. There is also encouraging evidence that cytokines can be targeted by orally active medicinal chemicals. This report offers an analysis of cytokine targets and therapeutics on the market or in development.

The increasing knowledge of the immune system has revealed a number of targets for specific regulation of immune cells and in particular the process of antigen presentation, lymphocyte activation and leukocyte chemotaxis. The disease modifying arthritis drug arava selectively suppresses lymphocyte activation by inhibiting nucleotide synthesis and new drugs with similar mechanisms of action are in development. Methotrexate remains one of the most widely used disease modifying drugs in rheumatoid arthritis and attempts are being made to discover improved anti-proliferatives that are more specific and better tolerated. Biologicals which block lymphocyte cell surface receptors thereby preventing activation or adhesion, and molecules that limit chemotaxic are also showing encouraging therapeutic activity; each of these areas is addressed in this report.

Pannus proliferation is a primary feature of rheumatoid arthritis and therefore the development of anti-proliferative agents represents an opportunity for treating this disease. Another strategy for obtaining the same result is the development of anti-angiogenic agents to prevent the vascularization of inflamed joint tissues. There is considerable overlap in this area with drugs being developed to treat cancer and this report continues with an analysis of approaches that may increase synovial apoptosis or reduce proliferation or angiogenesis.

One of the cardinal manifestations of rheumatoid arthritis is joint destruction. This feature results from the infiltration of various inflammatory cells into the pannus and the progression of synoviocytes into a phenotype that supports matrix destruction. This process involves the release of various proteases and the inhibition of these enzymes represents a further strategy in the treatment of rheumatoid arthritis. The report therefore concludes with an analysis of matrix metaloproteinases, elastases and cathepsins; how these enzymes contribute to disease progression and how the drug development sector is targeting these enzymes.

This report therefore overviews each of the major components of rheumatoid arthritis including cytokine production, leukocyte chemotaxis and adhesion, lymphocyte activation, synovial proliferation, angiogenesis and matrix degradation. In this overview we consider almost 50 molecular targets and more than 150 products being developed by nearly 100 companies therefore representing not only a complete analysis of current areas of research activity but also a thorough examination of therapeutic candidates emerging from this activity.

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