Brian Wong, M.D., Ph.D., director of research discovery in rheumatology at Roche Pharmaceuticals (www.roche.com), is focused on targeting key disease-critical pathways with small molecules at the preclinical stage. “We have learned a lot about RA in the last ten years, and this knowledge provides, in part, the underpinning of our discovery strategy.”
Roche has received recent approval in both the U.S. and Europe for using MabThera (rituximab) as a B-cell-selective treatment for RA. Originally developed as a treatment for B-cell lymphoma, said Dr. Wong, “MabThera targets CD20, which is specifically expressed on most B-cell populations,” and hence dampens B-cell accumulation in the RA-affected joint.
Actemra (tocilizumab) is another new product that inhibits the IL-6 receptor, which is responsible for systemic inflammatory responses mediated by both T and B cells. It is in Phase III trials for RA patients in both the U.S. and Europe.
“How these drugs work can tell you a lot about the pathophysiology of disease, and this has led Roche to target other genes in those pathways to find small molecules that will be cheaper to produce and orally available,” continued Dr. Wong.
A well known target in this effort is p38, “a kinase that is expressed fairly ubiquitously and broadly regulates cytokine signaling, including that mediated by TNF, IL-6, IL-1, and numerous others. Therefore by targeting p38, one may be able to replicate the anticytokine activity targeted by the biologics.”
T-5224, a AP-1 inhibitor in Phase I studies, was in-licensed by Roche from Toyama Chemical (www.toyama-chemical.co.jp). AP-1 is key in regulating inflammation and immune-cell function. “T-5224 blocks the ability of AP-1 to bind to DNA and induce the transcription of key inflammation genes such as cytokines.” Currently Roche is developing plans to test the agent in RA in its own studies.
Finally, Dr. Wong commented that companies continue to look for ways to enhance their drug discovery and development process. In the future, “monitoring the activity of key pathways in patients will help clinicians make better decisions during drug development.
“For example, one can monitor p38 activity in patients through directly measuring phosphorylation of p38 substrates in immune cells in blood.” In this way, the dosing of agents that interact with p38 can be much more fine-tuned to optimize safety and efficacy. Technologies such as phosphoflow cytometry enable quantification of multiple pathways in specific cell-types.