In a recent double-blind, placebo-controlled phase 3 trial, 100 patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid were randomly assigned to receive 400 mg of bezafibrate daily as adjuvant therapy, or placebo. Over 24 months, the primary outcome of complete biochemical response occurred in 31% of the intervention group and 0% of the placebo group. Complete biochemical response was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, plus a normal prothrombin index.
The trial was funded in part by industry and was published June 7 by the New England Journal of Medicine. The following commentary by Jacob Korula, MD, FACP, appeared in the ACP Journal Club section of the Oct. 16 Annals of Internal Medicine.
Over 2 decades, URSO (ursodeoxycholic acid) has been the mainstay for treating PBC (primary biliary cholangitis). Efficacy in normalizing liver tests and delaying transplant in early disease is overshadowed by lack of benefit in advanced disease or for transplant-free survival or mortality. Although PBC is considered an autoimmune disease, immunosuppressive drugs are ineffective. Obeticholic acid therapy is limited by pruritus in >30% of patients, and the search for alternative treatments in patients who are unresponsive to URSO has led to evaluation of fibrates for this disease.
How do fibrates work? Ghonem and colleagues show that ligand activation of the nuclear receptor, peroxisome-proliferator-activated receptor-α (PPARα), at the canalicular membrane inhibits nuclear factor κ-light-chain-enhancer of activated B-cells, tumor necrosis factor-α, and interleukins to reduce inflammation. Reduction of bile acid synthesis by down-regulation of cytochrome P7A1 and up-regulation of the canalicular-transporter ATP- binding cassette–4 encoding multidrug resistance protein 3 results in increased biliary phosphatidylcholine secretion and mixed micellization of bile acids. These and other complex mechanisms collectively reduce cholestasis.
In 1999, the observation that bezafibrate improved serum transaminases and alkaline phosphatase levels led to therapeutic trials that showed benefits with fenofibrate and bezafibrate (which activates all 3 isoforms, PPARα,β/δ,γ) and are summarized in meta-analyses.
In the trial by Corpechot and colleagues, 39% of patients had stage 3 or 4 disease and only 31% achieved the primary outcome with bezafibrate. During follow-up, progression to portal hypertension was seen in small numbers of patients in both groups, perhaps attesting to lack of efficacy in advanced disease and to the indolent course in most PBC patients. Although bezafibrate is unavailable in the USA, fenofibrate can be offered off-label with close monitoring of adverse effects. Time will tell whether its effects are similar. For the moment, at least we have another treatment option.