I just returned from the American College of Rheumatology Annual Scientific Meeting in San Francisco. And while there is no doubt I will miss the City, there is also a fairly equal certainty that the future of rheumatoid arthritis treatment was well-addressed.
It appears that the next major advance in the treatment of rheumatoid arthritis will be the oral small-molecule drugs. These drugs will target different enzyme pathways, which, if left unmolested, result in the inflammation that characterizes rheumatoid arthritis. These drugs are even more precise than today's existing "biologic" drugs, such as Enbrel and Humira; the new small-molecule drugs will actually attack inflammatory mediators inside the cell.
On the practical side, these oral drugs have the further advantage of convenience (that is, no "messy" injections or long infusions while sitting in a chair in the doctor's office) and cost (a pill is less expensive compared to the injection equipment of today's biologics).
There are several pathways found inside the cell which can contribute to autoimmune disease such as rheumatoid arthritis:
1. The Janus kinase (JAK) 3. At the meeting, results of studies were presented on the first JAK inhibitor, CP-690, 550. This oral drug inhibits JAK3, and it was found to be a well-tolerated and effective long-term treatment for patients with moderate to severe rheumatoid arthritis. Significant responses were noted as early as the third week of treatment. However, there does appear to be some adverse impact on white blood cell counts, and cholesterol levels. These laboratory abnormalities appear to be dose-dependent, so more study will have to be done to discover the best dose for treating the arthritis - without causing other problems.
2. The JAK 1 and 2. Another drug, INCB018424, inhibits JAK 1 and 2. This drug also appeared to be well-tolerated and effective. There did not appear to be decreases in blood counts at the dosages tested.
3. Syk kinase. This is another protein in cells which plays a role in activating cells involved with immunity; an aspect of this is accomplished through the activation of some JAK proteins. The oral drug R788 is an inhibitor of Syk kinase, and it certainly had a profound effect on patients with rheumatoid arthritis, as improvement was noted as early as the first week; and up to one-half of the patients treated with the highest dosage were in remission three months after treatment. Side effects included diarrhea and a drop in the white blood cell count.
4. P38 mitogen-activated protein kinase (MAPK). This enzyme is in cells, and it responds to tissue injury, by increasing the production of inflammatory biochemicals. SCIO-469 is an oral drug which inhibits the p38 MAPK. Unfortunately, this study did not show any positive effect on rheumatoid arthritis after 12 weeks.
These drugs are new, and the data certainly early. However, many researchers see these new oral medications as the future of rheumatoid arthritis treatment. Time and research will tell. I look forward to forwarding results of further research as they are presented.
In the meantime, San Francisco and those oral small-molecule drugs have certainly left me hungry for more.
Published On: November 10, 2008