Study of children with the inflammatory bowel disorder raises possibility of new use for tainted drug
The ongoing repurposing of the infamous drug thalidomide may include treatment of Crohn’s disease, an incurable bowel condition. Thalidomide was banned or never approved in many countries because it caused thousands of severe birth defects when pregnant women took it in the late 1950s and early 1960s. But researchers have now shown it can knock out symptoms in pediatric Crohn’s patients, sending the disease into remission in most cases.
Crohn’s is an inflammatory bowel disease marked by diarrhea, abdominal pain, weight loss and vomiting. One-fourth of cases show up in childhood. Crohn’s affects roughly 500,000 people in the United States and 1.2 million in Europe.
Starting in 2008, Marzia Lazzerini of the Institute for Maternal and Child Health in Trieste, Italy, and her colleagues randomly assigned 54 children with Crohn’s to get daily thalidomide or a placebo. Many of the children were also taking steroids to reduce inflammation. All had failed to improve on other medications. Their average age was in the mid-teens.
After the eight-week trial, 13 of 28 kids who got thalidomide were in remission and five others had substantially fewer symptoms. Three of 26 children getting the placebo also went into remission, and two others needed surgery. The researchers then offered thalidomide to the other 21 placebo recipients, 11 of whom went into remission within eight weeks.
The researchers then extended the trial, offering thalidomide long-term to patients who had shown some benefit and hadn’t experienced any severe side effects. Overall, 31 of 49 children taking thalidomide achieved remission. After one year, 30 were still free of disease. Sixteen weeks into the extended phase, all children still taking the drug had stopped using steroids. During the trial extension, doctors gradually decreased the daily thalidomide dose.
The average time in remission for these patients was 3.5 years, the scientists report in the Nov. 27 JAMA. One patient has been taking thalidomide for five years, Lazzerini says.
“This is a well-designed study, no doubt about that,” says W. Douglas Figg, a pharmacologist at the National Cancer Institute in Bethesda, Md., who has investigated thalidomide use against cancer. “I’m glad to see the activity it has shown here. There’s very little out there for [treatment of] Crohn’s disease.”
Thalidomide was effective in many children who had failed to improve while taking infliximab (Remicade), a frontline drug against Crohn’s. Both drugs neutralize an inflammatory protein called tumor necrosis factor-alpha, or TNF-alpha, but thalidomide also thwarts the formation of new blood vessels. That action is thought to have caused the birth defects.
Thalidomide also exerts many other effects in the body, Figg says, and that has scientists intrigued. Hundreds of clinical studies testing the drug are under way. Thalidomide is approved by the Food and Drug Administration for treatment of a complication of leprosy and a blood cancer called multiple myeloma, but its history remains a red flag.
“There is clearly a concern that’s always there,” Figg says. In nine instances, a child in the new study experienced a side effect severe enough to require the patient to stop taking thalidomide. The most common problem was peripheral neuropathy, damage to nerves away from the brain and spinal column.
M. Lazzeriniet al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: A randomized clinical trial. JAMA. Vol. 310, November 27, 2013, p. 2164. doi:10.1001/jama.2013.280777.
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