From the AGA Journals

Bezafibrate eased pruritus in patients with fibrosing cholangiopathies

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‘New generation’ of cholestatic itch trials

Itch really matters to patients with cholestatic liver diseases, and effective treatment can make a significant difference to life quality. Although therapies exist for cholestatic itch (such as cholestyramine, rifampin, and naltrexone) recent data from the United Kingdom and United States suggest that therapy in practice is poor. It is likely that this results, at least in part, from the limitations of the existing treatments which can be unpleasant to take (cholestyramine) or difficult to use because of monitoring needs and side-effects (rifampin and naltrexone). Itch has therefore been identified as an area of real unmet need in cholestatic disease and there are a number of trials in progress or in set-up. This is extremely positive for patients.

Dr. Dave Jones is a professor of liver immunology at Newcastle University, England.

Dr. Dave Jones

The FITCH trial is one of the first of these “new generation” cholestatic itch trials to report and explore the efficacy of the PPAR-agonist bezafibrate in a mixed cholestatic population. Clear benefit was seen with around 50% of all disease groups meeting the primary endpoint and good drug tolerance. Is bezafibrate therefore the answer to cholestatic itch? The cautious answer is ... possibly, but more experience is needed. The trial duration was only 21 days, which means that long-term safety and efficacy remain to be explored. Bezafibrate is now being used in practice to treat cholestatic itch with effects similar to those reported in the trial. It is therefore clearly an important new option. Where it ultimately ends up in the treatment pathway only time and experience will tell.

David Jones, BM, BCh, PhD, is a professor of liver immunology at Newcastle University, Newcastle Upon Tyne, England. He reported having no disclosures relevant to this commentary.


 

FROM GASTROENTEROLOGY

Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).

Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.

Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).

Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”

The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.

There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.

Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m2, one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.

The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.

SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.

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