Treatment with bezafibrate proved superior to placebo in a small randomized trial for short-term relief of moderate to severe cholestasis-associated pruritus in patients with fibrosing cholangiopathies.
The primary endpoint of a more than 50% reduction in severe or moderate pruritus at 21 days was achieved by 45% of patients in the arm given the lipid-lowering drug bezafibrate versus 11% in those receiving placebo (P=0.003), according to Ulrich Beuers, MD, of the Tytgat Institute for Liver and Intestinal Research at Amsterdam University Medical Center in the Netherlands, and colleagues.
As reported in Gastroenterology, for secondary endpoints, bezafibrate reduced the intensity of both morning (P=0.01) and evening (P=0.007) pruritus versus placebo on a visual analog scale (VAS) and also improved scores (P=0.002) on a validated itch scale questionnaire of five dimensions (degree, duration, direction, disability, and distribution).
The researchers explained that in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), bezafibrate can be considered a new treatment option for cholestasis-associated pruritus due to its anti-pruritic and anticholestatic properties and favorable safety profile. Further prospective studies, however, are needed to confirm the long-term efficacy and safety.
As the authors pointed out, pruritus can seriously impair quality of life in patients with cholestatic diseases, and pharmacological strategies have shown limited efficacy and sometimes serious side effects.
“We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury,” the investigators wrote.
Suthat Liangpunsakul, MD, MPH, of Indiana University School of Medicine in Indianapolis, who was not involved with the study, called the results promising for this common but difficult-to-treat condition. “Once cholestasis develops, effective therapies, either to treat underlying liver disease or itching, are limited,” he told MedPage Today.
“Overall, this study provides us a new insight into the possible role of bezafibrate as part of a treatment algorithm for pruritus in patients with cholestatic liver disease. This compound may also be beneficial for improving underlying cholestasis and hepatobiliary damage, though this is a speculation,” he continued.
The major limiting factor, Liangpunsakul said, was the treatment’s short duration, with the severity of itching rebounding at day 35, 2 weeks after the end of bezafibrate therapy. “Therefore, I would view this as a pilot proof-of-concept study on the use of this drug for pruritis. Long-term treatment intervention to further evaluate its safety profile and efficacy is certainly needed,” he said.
For the study, called Fibrates for Itch (FITCH), patients at least 18 years old with severe or moderate pruritus from cholestasis caused by PBC, PSC, or secondary sclerosing cholangitis (SSC) (as defined by European Association for the Study of the Liver clinical practice guidelines) were recruited from 2016 to 2019 at one Spanish and seven Dutch academic hospitals.
Eligible participants twice reported an itch intensity on VAS of at least 5 out of 10 (0 = no itch, 10 = worst itch possible) within the week before inclusion.
Of 74 patients randomized to once-daily bezafibrate at 400 mg (38 patients) or placebo (36 patients) for 21 days, 70 completed the trial: 44 with PSC, 24 with PBC, and two with SCC.
Of these, 22% and 23%, respectively, were female in the intervention and placebo arms, while the mean ages were 46 and 50, respectively.
By cholangiopathy type, 41% of patients with PSC and 55% with PBC achieved the primary targeted reduction. The median pruritus VAS score decreased in the bezafibrate group to 4.0 at day 21 but returned to 7.0 at day 35, which was 2 weeks after treatment cessation.
The median VAS score remained 7.0 at day 21 in the placebo group and fell to 6.5 at day 35 (P<0.001 between the two groups on day 21).
Bezafibrate also reduced the level of serum alkaline phosphatase (–35%, P=0.03 vs placebo) correlating with improved pruritus on VAS (P=0.01) and suggesting reduced biliary damage, the researchers reported.
Serum bile acids and activity of the fibrosis-associated enzyme autotaxin remained unchanged in both arms during the study, with autotaxin showing no correlation with reduction in pruritus. Serum creatinine levels, however, tended to increase slightly – by 3% with bezafibrate and 5% with placebo (P=0.14).
While no serious adverse events (AEs) were reported, six AEs were documented in six patients — one in the placebo group (dizziness) and five in the bezafibrate group (intensified itch and jaundice after treatment cessation in two patients, as well as mouth and lower back pain and general malaise). In addition, five AEs were considered unrelated to the study medication, while one (mouth pain) was considered possibly related to bezafibrate, the team said.
A mounting body of evidence has suggested that this lipid-lowering drug is beneficial in cholestatic disease. For example, the French BEZURSO study found that adding bezafibrate to ursodeoxycholic acid normalized liver enzymes in PCB patients.
A 5% increase in serum creatinine, however, from baseline after 3 months of bezafibrate was reported in BEZURSO patients, but this measure remained largely stable during continued treatment.
In addition, 20% of BEZURSO participants experienced myalgia (vs 10% with placebo), and 6% showed an alanine transferase elevation of more than five times the upper limit of normal compared with 2% with placebo.
FITCH study limitations, the authors said, included its short 3-week duration and the recruitment of just 74 rather than the targeted 84 patients.
The study was funded by grants from a South African primary sclerosis cholangitis patient foundation, a Netherlands patient donation, the Netherlands Society of Gastroenterology, and the Instituto de Salud Carlos III.
Beuers and co-authors reported having no competing interests relevant to the study.
Liangpunsakul reported having no competing interests with respect to his comments.