Drug Found to Be Safe in Pbc Patients Not Responsive to Ursodeoxycholic Acid
An open-label study of rituximab, a monoclonal antibody for human CD20,
was shown to be safe in patients with primary biliary cirrhosis (PBC)
who had an incomplete response to the standard ursodeoxycholic acid
(UDCA) therapy, also known as Ursodiol. Study details available in the
February issue of Hepatology,
a journal published by Wiley-Blackwell on behalf of the American
Association for the Study of Liver Diseases, report that rituximab was
successful in reducing the level of alkaline phosphatase (ALP)—a protein
used to measure liver injury.
According to the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK), PBC—an autoimmune liver disease characterized by
inflammation of the bile ducts that ultimately causes bile to build up
and damage the liver—typically occurs between the ages of 40 and 60,
primarily affecting women. Medical studies have identified the presence
of anti-mitochondrial autoantibodies (AMA) to enzymes involved in the
production of the body’s energy (pyruvate dehydrogenase complex-PDC-E2)
in up to 95% of PBC cases.
Currently, the standard therapy for PBC is UDCA or liver transplantation
in patients who have progressed to end-stage liver disease. However,
previous studies have shown that UDCA may be ineffective in up to 40% of
PBC patients and 10% could require transplantation or die from the
disease. “Small trials using immunosuppressants have failed to
demonstrate significant clinical benefit or carry unacceptable safety
profiles,” said Dr. Christopher Bowlus with UC Davis Health System in
California and lead author of the current study.
Dr. Bowlus added, “Given our previous work implicating B cells to the
development of this disease, we hypothesized that a therapy such as
rituximab, which depletes B cells, could offer a potentially effective
treatment option with acceptable adverse effects.” The team enrolled 6
patients between the ages of 18 and 65 years of age who were diagnosed
with PBC and had an incomplete response to UDCA despite 6 months of
therapy. Participants in this open-label study received an intravenous
infusion of 1000 mg of rituximab on day 1 and day 15, with follow-up for
52 weeks. Two patients received one dose of rituximab due to latent
varicella (chickenpox) activation in one and viral respiratory infection
in the other.
The trial results found that rituximab was safe and well tolerated by
PBC patients, with no serious adverse events reported. By 16 weeks
post-treatment patients had significantly lower levels of
immunoglobulins IgG, IgM, and IgA, which are the antibodies normally
present in blood, but in the case of IgM are often elevated in PBC. In
addition, the abnormal antibodies directed against mitochondria (AMA),
were also reduced after treatment. However, levels returned to baseline
by 36 weeks. Further, serum alkaline phosphatase decreased up to 36
weeks post-treatment.
The authors noted that rituximab therapy could clinically improve PBC
through multiple pathways that include the reduction of
anti-mitochondrial antibodies through depletion of memory B cells,
increases in regulatory T cells associated with immune response, and
modulation of cytokine production involved with inflammation. “Further
investigation of B cell targeting strategies is necessary to develop
potentially novel therapeutic options for patients with PBC,” concludes
Dr. Bowlus.
