Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.
Moderate to severe pruritis “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.
“Finally having a medication that controls those symptoms is really important,” she told Medscape Medical News.
With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Levy reported at The Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.
After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens — once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg or twice-daily doses of 40 mg or 90 mg — or to placebo.
After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.
During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.
The primary study end point was the change in worst daily itch from baseline to week 16. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.
Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.
Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40 mg twice-daily group, at 2.86 points, and in the 90 mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.
During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.
Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40 mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
“Between Incremental and Revolutionary”
The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, from the University of Arkansas for Medical Sciences in Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”
The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritis is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo,” he said.
The placebo effect in itching studies is always high but tends to wane over time, said Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.
About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.
Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Levy.
It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Danoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”
The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”
Levy discloses support from GlaxoSmithKline. Danoff has disclosed no relevant financial relationships.
The Liver Meeting Digital Experience 2020: American Association for the Study of Liver Diseases (AASLD): Abstract LP38. Presented November 13, 2020.