The researchers found that the buildup of lymph fluid is actually an inflammatory response within the tissue of the skin, not merely a “plumbing” problem within the lymphatic system, as previously thought.
Working in the lab, scientists discovered that a naturally occurring inflammatory substance known as leukotriene B4, or LTB4, is elevated in both animal models of lymphedema and in humans with the disease, and that at elevated levels it causes tissue inflammation and impaired lymphatic function.
Further research in mice showed that by using pharmacological agents to target LTB4, scientists were able to induce lymphatic repair and reversal of the disease processes.
“There is currently no drug treatment for lymphedema,” Tian said. Based on results of the study, the drug bestatin, which is not approved for use in the United States but which has been used for decades in Japan to treat cancer, was found to work well as an LTB4 inhibitor, with no side effects, she said.
Based on the research, bestatin (also known as ubenimex), is being tested in a clinical trial that started in May 2016 — known as ULTRA — as a treatment for secondary lymphedema, which occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or infection. Primary lymphedema, on the other hand, is hereditary. The results of the research pertain to both types.
Rockson is principal investigator for this multisite phase-2 clinical trial.
“The cool thing about this story — which you almost never see — is that a clinical trial testing the therapy has already started before the basic research was even published,” Nicolls said. “This is the first pharmaceutical company-sponsored trial for a medical treatment of lymphedema, a condition that affects millions.”
Nicolls and Tian are co-founders of Eiccose LLC. Eiccose is now part of Eiger BioPharmaceuticals, which gets the drug from Nippon Kayaku in Japan. Eiger is sponsoring the clinical trial. Nicolls and Rockson are both scientific advisers to the company.