Rheumatoid arthritis - ISIS 104838
Rheumatoid arthritis is an autoimmune disease, and is the second most common form of arthritis. It affects the synovial lining of the joints. To start with, the joints become stiff, swollen and painful, but as the disease progresses, bone erodes and the ligaments that support the joints are damaged as enzymes are released from inflammatory cells that digest both bone and cartilage. It can even affect tendon sheaths, leading to rupture of the tendons. Women are disproportionately affected.
ISIS has been investigating TNF-alpha as a target for the drug treatment of rheumatoid arthritis. TNF-alpha is a naturally occurring cytokine that contributes to the activity and progression of a variety of inflammatory diseases, and high blood concentrations have been found in patients with rheumatoid arthritis, as well as those with Crohn's disease, multiple sclerosis, psoriasis and congestive heart failure, among others.
In rheumatoid arthritis, TNF-alpha stimulates bone and cartilage resorption, and also drives the inflammatory process. The company has identified an antisense oligonucleotide, ISIS 104838, that is specific for TNF-alpha mRNA, inhibiting the synthesis of TNF-alpha itself. The potential drug is the first based on ISIS's proprietary 2'-O-methoxyethyl derivatisation chemistry to enter clinical trials.
In a Phase I trial, a group of healthy males were given multiple intravenous infusions of ISIS 104838 in doses of 0.1 to 6mg/kg or placebo in a placebo-controlled dose escalation study.1 Further healthy volunteers were given the drug in single or multiple subcutaneous injections. ISIS 104838 suppressed TNF-alpha protein by 85% in stimulated keratinocytes. The pharmacokinetic results of the trial supported an infrequent dosing interval, and it was well tolerated when administered both intravenously and subcutaneously.
Phase II trials are under way. The company is also developing an oral dosage form, and a capsule formulation has been shown to give sufficiently good plasma concentrations to warrant further clinical development.2 The company is also investigating a topical formulation as a potential treatment for psoriasis.