DMARDs in Development

Drugs in development for Rheumatoid Arthritis
Copyright Veritas Medicine
Used here with permission

DMARDs

Disease-modifying anti-rheumatic drugs (DMARDs) make up a large family of drugs used to treat rheumatoid arthritis (RA). In order to be classified as a DMARD, a drug must be shown to improve the symptoms of RA for at least one year and must act in a different way than corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs). DMARDs improve joint function and, since they work by different processes than NSAIDs, they generally are prescribed in combination with NSAIDs.

Until recently, little was known about how these drugs work to alleviate the symptoms of RA. However, we now have a better understanding of the biology of RA and some insight into how these drugs work. As a result, a new generation of DMARDs is being developed that are more effective and have fewer side effects.

Experimental DMARDs can be organized into six categories:

Anti-metabolites Cytokine inhibitors Protease inhibitors Chemotaxis inhibitors Complement inhibitors Others

1) Anti-metabolites

Anti-metabolite DMARDs work by blocking various metabolic steps required to make DNA or other important molecules involved in building new cells. When immune cells are activated to attack the joints in RA patients, the immune cells undergo massive growth. Thus the effect of anti-metabolite DMARDs is to block DNA production and cell growth in immune cells. However, since DMARDs inhibit DNA production in all cells, not just immune cells, these drugs are associated with serious side effects. The best known among this group of drugs is methotrexate.

The following drugs are anti-metabolites in development:
MX-68
PT-523
Pentostatin injection

2) Cytokine inhibitors

Cytokines are a group of proteins that regulate the immune system's activity. In general, cytokines can either stimulate or stifle the immune response. Two important cytokines, Tumor Necrosis Factor (TNF)-alpha and Interleukin-1 (IL-1), help orchestrate the active phases of RA. Interestingly, these cytokines are found in the joints of all RA patients. Research aimed at inhibiting the activity of these cytokines has resulted in a number of promising drugs.

The following drugs are cytokine inhibitors in development:
EF-5, Diacerein, IGF-1, IL-1 Hy1 and IL-1Hy2, ICE Inhibitors, VX-740, D2E7, IL-1ra, KB-R7785, CDP870, Teva TNF-Alpha Inhibitor, and Scios P38-Kinase Inhibitors.

3) Chemotaxis inhibitors

Chemotaxis inhibitors are DMARDs that work by interfering with the chemical signals that attract inflammatory cells to joints, thereby limiting the damaging effects they can cause. If inflammatory cells are prevented from detecting these chemical signals they will be less likely to migrate to and damage the joints. Although still in the early stages of development, chemotaxis inhibitors will hopefully play a role in the treatment of RA.

The following drugs are chemotaxis inhibitors in development:
CCR1 antagonist
PD172084
CXCR3 Antagonist

4) Complement inhibitors

Complement inhibitors are a class of DMARDs that interfere with the complement system, a key component of the body's immune defenses. The complement system consists of proteins that interact through a cascade of complex reactions, the final product of which can destroy bacteria and foreign cells. During these complex reactions, small proteins are generated that have inflammatory effects on blood vessels. These small complement proteins also recruit immune cells to the joints of the RA patient, thereby contributing to the inflammatory process. Activation and progression of this complement cascade normally proceeds in a tightly regulated fashion. When this process proceeds without the normal level of regulation, it may result in the destruction of healthy cells and may also contribute to ongoing inflammation. Although still in the early stages of development, drugs directed against various components of the complement system may play a role in the reduction of damage to the joints and other tissues of RA patients.

The following drug is a complement inhibitor in development:
5G1.1

6) Others

This subset includes DMARDs that are in development and have mechanisms of action that are diverse and incompletely understood.

The following drugs are miscellaneous DMARDs:
CBF-BS2
IPL-423088
Apogens