Crohn's Disease Treatment Shows Promise in Clinical Trial
In a small, initial clinical trial led by the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health, doctors found that up to 75 percent of people
with Crohn's disease responded to an experimental new treatment,
and up to 50 percent had long-term remission of symptoms. They report
these findings in the Nov. 11 issue of The New England Journal of
Crohn's, which affects an estimated 500,000 Americans, is an autoimmune
disease that attacks the bowels, causing abdominal pain, cramping,
diarrhea and rectal bleeding. In severe cases, damaged bowel sections
must be surgically removed.
The new treatment is an antibody designed to disable interleukin-12
(IL-12), an immune system protein involved in inflammation. People
with Crohn's produce excess IL-12. Previous studies by NIAID researcher
Warren Strober, M.D., linked IL-12 to the cascade of immune system
events that leads to the debilitating symptoms of Crohn's disease.
"NIAID researchers have taken advantage of a potential target
for preventing, early in the disease process, the devastating inflammation
that excess IL-12 seems to trigger. Existing treatments, which often
fail, attempt to interrupt inflammation far later in the process,"
says Anthony S. Fauci, M.D., director of NIAID. "This is the
first test of this potential new treatment in people with Crohn's
disease, and we are encouraged by the results."
The clinical trial was conducted at 15 centers in the United States,
Germany and the Netherlands. Peter Mannon, M.D., and Ivan Fuss,
M.D., of NIAID led the study, which enrolled 79 men and women with
Crohn's disease. Most study volunteers were randomly assigned to
groups where they were injected with either low- or high-dose antibody
treatments on one of two possible dosing schedules. The remaining
sixteen volunteers received placebo injections.
The treatment consisted of a human antibody genetically modified
to attach to and disable IL-12. High IL-12 levels in people with
Crohn's disease activate T cells, which in turn produce a variety
of proteins-interferon, tumor necrosis factor, IL-6 and IL-18-that
cause damage in Crohn's disease.
After seven injections given weekly, 75 percent of 16 people receiving
the higher dose of anti-IL-12 antibody responded to the treatment.
At the end of the 24-week trial, six of those volunteers' symptoms
were in remission.
Other volunteers received seven injections, with four weeks between
the first and second injection, followed by six weekly injections.
In this group, 56 percent (9 of 16 people) receiving the higher
dose had responded to the treatment at week nine. At the end of
the 18-week follow-up phase, half of these responders had remission
of their symptoms.
The researchers also measured levels of the other immune system
proteins-interferon, tumor necrosis factor, IL-10, IL-6 and IL-18-that
are produced by the activated T cells in eight volunteers who received
treatment at the National Institutes of Health Clinical Center.
The researchers measured the proteins before and after treatment
and found that many of the inflammatory proteins had dropped dramatically
by the end of treatment. The decline in these proteins suggests
that blocking IL-12 worked as the doctors hoped it would, by slowing
or halting the Crohn's disease process.
"Data from this early study show us that the treatment was
safe and also provide evidence that the antibody treatment may be
effective against inflammation in Crohn's disease. The next step
is to test the treatment in a larger group of volunteers and seek
the most effective dose and treatment schedule," says Dr. Mannon.
Abbott Laboratories produced the anti-IL-12 antibody. Another pharmaceutical
company, Wyeth, and the National Cancer Institute, also part of
NIH, contributed to study costs.
NIAID is a component of the National Institutes of Health, an
agency of the U.S. Department of Health and Human Services. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on transplantation
and immune-related illnesses, including autoimmune disorders, asthma
and allergies. News releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: PJ Mannon et al. Anti-interleukin-12 antibody for active Crohn's disease. The New England Journal of Medicine 351(20):21-31 (2004)-double check page numbers