Biological engineers discover why a promising drug failed in clinical trials
Pharmaceutical companies once considered a protein called p38 a very attractive target for treating rheumatoid arthritis. Arthritis patients usually have elevated activity of this inflammation-producing protein, and in lab studies p38 inhibitors appeared to soothe inflammation. However, these drugs failed in several clinical trials.
A new study from
The findings demonstrate the importance of studying a potential drug`s impact on complex cellular systems, says
"You`ve got to make sure you understand the complexity of the intracellular networks, and beyond that, you need to think about the environment you put the cells in," Lauffenburger says. "It`s easy to get different results in different contexts, so you need to study them under many different conditions."
A promising target
Rheumatoid arthritis, which afflicts more than 1 million Americans, is an autoimmune disorder that produces swollen and painful joints, primarily affecting the wrists and hands. This pain results from inflammation in the lining of the joints. Cells called synovial fibroblasts, which typically provide structural support for the joint lining, promote the inflammation and swelling in arthritic conditions.
Several years ago, scientists seeking new treatments for arthritis discovered that synovial fibroblasts from arthritis patients had very high levels of p38, and many pharmaceutical companies began working on p38 inhibitors. "The activity of this pathway was so strong that people tended to think that it was the best one to inhibit," Lauffenburger says.
Despite their promise, p38 inhibitors failed in phase II clinical trials run by at least eight pharmaceutical companies. One of those companies,
The researchers` analysis revealed that the inflammatory pathway controlled by p38 interacts with several other pathways that can cause inflammation. These pathways, known collectively as stress pathways, produce inflammatory cytokines in response to events such as infection or injury.
"This is an insightful paper on redundancy in signaling and the need to understand compensatory mechanisms before spending billions on drug development. In that sense, it is a far more important insight than `just` p38 inhibitors, and it makes clear again that animal efficacy models have severe limitations as tools to predict human efficacy," says
Why was the
Normally, cells studied in the lab are grown in a culture medium that offers them nutrients and molecules called growth factors, which keep the cells alive and proliferating. However, the
"It looks like p38 inhibitors work well, if cells are in these growth factor environments," Lauffenburger says.
One question still to be answered is whether p38 inhibitors could work against other diseases such as cancer, in which the cells targeted would likely be in a pro-growth environment. They are also being considered as potential treatments for other inflammatory diseases such as multiple sclerosis and Alzheimer`s. Lauffenburger says that their success will likely depend on what kind of environment the affected cells are in.
"A p38 inhibitor could work; you just have to know what the context is that the target cells are in. If you have the same kind of inflammatory cytokines there, then you might encounter the same problem" seen in arthritis, he says.
It`s also possible that p38 inhibitors could work against arthritis or other drugs if given along with drugs that shut off other stress pathways, but more research would be needed to investigate that possibility, Lauffenburger says.