07 Jun Bezafibrate: Potential Treatment for PBC and Itching From Biliary Disease
MedicalResearch.com Interview with:
Dr Christophe Corpechot
Centre de Référence Maladie Rares: Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes (MIVB-H)
Filière Maladies Rares: Maladies Rares du Foie de l’Adulte et de l’Enfant
Hôpital Saint-Antoine (APHP) et Sorbonne Universités
MedicalResearch.com: What is the background for this study?
Response: Primary biliary cholangitis (PBC, previously known as “primary biliary cirrhosis”) is a rare, chronic, slowly progressive liver disease of unknown cause, mainly affecting women of middle age. It is characterized by serum marks of autoimmunity (specific auto-antibodies), chronic inflammation and destruction of small intra-hepatic bile ducts, and consequent bile secretion impairment (chronic cholestasis) leading to the progressive development of cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) is the only first-line approved treatment for PBC. It improves the biochemical measures of cholestasis and prolongs survival without liver transplantation. However, 30% to 40% of UDCA-treated patients continue to have clinically significant abnormalities of their biochemical liver tests and those patients remain at high risk of developing end-stage liver disease complications.
Recently (2016), obeticholic acid (OCA) in association with UDCA has been conditionally approved in patients with an inadequate response to UDCA. This approval (FDA, EMA) was based one the results of a 1-year randomized, double-blind, placebo-controlled trial of OCA in patients with an incomplete response or intolerance to UDCA (POISE trial). In this trial, OCA was shown to improve the biochemical features of cholestasis (alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range and a reduction of at least 15% from baseline) but was associated with a significant increase of pruritus, a characteristic, potentially debilitating symptom of PBC. BEZURSO is the first ever placebo-controlled phase 3 trial of a fibrate (a class of drugs known to be agonists of the peroxisome proliferator-activated receptors alpha) in PBC. In this 2-year randomized double-blind trial, 100 patients with an incomplete response to UDCA were assigned to bezafibrate 400 mg/day (n=50) or placebo (n=50), all in association with continued UDCA therapy.
MedicalResearch.com: What are the main findings?
Response: The primary endpoint (normal levels of total bilirubin, ALP, transaminases, albumin and a normal prothrombin index, a derived measure of the prothrombin time, at 24 months) was reached in 31% of patients in the bezafibrate group and 0% in the placebo group (p<0.001). Two thirds of the patients in the bezafibrate group normalized their ALP level at 24 months. In contrast to the POISE study, these results were associated with a significant, parallel improvement in the patient-reported outcomes (pruritus, fatigue) and non-invasive measures of liver fibrosis (liver stiffness measurement, Enhanced Liver Fibrosis score). However, like in POISE, the trial was not large or long enough to assess the effect of the drug on long-term clinical outcomes, as transplantation or death. Bezafibrate was well tolerated (the groups did not differ according to adverse effects and serious adverse effects) but a 5% increase of serum creatinine level was observed in the bezafibrate group in complete accordance with the well-known safety profile of the drug.
MedicalResearch.com: What should readers take away from your report?
Response: The BEZURSO results extend the therapeutic options in patients with PBC who have an inadequate response (or intolerance) to UDCA. In this condition, bezafibrate appears to be biochemically as effective as OCA, even if a direct comparison is lacking. Furthermore, bezafibrate is the first treatment in PBC to show concomitant improvement in biochemistries, symptoms, and surrogate markers of liver fibrosis, suggesting that the effects of the drugs are real and not only cosmetic. Bezafibrate should also be now considered among the potential therapeutic strategies in patients with cholestatic pruritus. The use of bezafibrate should be evaluated taking renal function into consideration. Bezafibrate is inexpensive (7 euros a month) and its cost is more than 400 times lower than that of OCA.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Longer studies are required to prove the effects of bezafibrate on clinical outcomes and to collect long-term data on renal safety. However, these studies are unlikely to be conducted in the future (limited market, inexpensive drug, lack of expected industrial support). Please note that according to the prognostic models (Globe score, UK-PBC score), bezafibrate treatment is expected to reduce by 40% the incidence of liver transplantation or death at 15 years. Furthermore, the meta-analyses of bezafibrate conducted in patients with diabetes did not show an increased risk of end-stage kidney disease.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Bezafibrate is available in Europe and Asia, but not in the US and Australia. Fenofibrate, which showed similar biochemical effects in small pilot studies, may be an alternative option for the US and Australian patients.
A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis
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