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BOSTON -- An investigational dual peroxisome proliferator-activated receptor (PPAR) agonist appeared effective as a second-line option for primary biliary cholangitis (PBC), according to phase III trial results.

Investigators found that 51% of patients randomized to oral elafibranor achieved a biochemical response indicative of a reduction in cholestasis at week 52, as compared with just 4% of those assigned placebo (P<0.001), reported Christopher Bowlus, MD, of the University of California Davis School of Medicine in Sacramento.

Responses -- measured as reductions in alkaline phosphatase (ALP) -- occurred rapidly, and treatment with the dual PPAR alpha/delta agonist was safe and demonstrated potential anti-pruritic benefits.

"Thus, elafibranor may provide an effective new treatment for patients with PBC," Bowlus said during a late-breaking abstract session here at the annual Liver Meeting sponsored by the American Association for the Study of Liver Diseases.

PBC is a rare, chronic cholestatic liver disease that is increasing in prevalence and occurs predominantly in women ages 40 and older. If left untreated, the condition can progress to cirrhosis, lead to the need for liver transplantation, and result in premature death.

In the current study -- results of which were published simultaneously in the -- nearly all patients had a suboptimal response to ursodeoxycholic acid (UDCA), a tertiary hydrophilic bile acid that represents the only approved first-line therapy for PBC. Up to 40% of patients have an inadequate response to this treatment, and 3-5% of patients cannot tolerate it as well.

While obeticholic acid (Ocaliva) is approved as a second-line treatment, only half of patients respond to the drug, and it is associated with exacerbation of pruritus, which is among the most common symptoms reported by PBC patients and which can severely impact their quality of life.

In their paper, the researchers explained that elafibranor "decreases the toxic effects of bile acid and inflammation through downstream modulation of the nuclear receptor targets" of PPAR alpha and delta, with prior phase II findings demonstrating improvements in ALP, a trend toward decreased pruritus, and no safety concerns.

Bowlus presented findings from the multinational phase III trial, with data analysis including 161 patients randomized 2:1 to either once-daily elafibranor (80 mg) or placebo. The primary endpoint of biochemical response was defined as an ALP of less than 1.67 times the upper limit of normal (with a reduction of at least 15% from baseline) and normal total bilirubin levels at week 52.

At enrollment, most patients (95%) had an inadequate response to UDCA, and this group continued concurrent UDCA treatment along with the intervention, while patients unable to tolerate UDCA received only elafibranor or placebo.

Overall, 96% of the patients were women, 91% were white, and their mean age was 57 years. At baseline, patients had had their PBC diagnosis for 8 years on average, 41% had moderate-to-severe pruritus, and mean ALP was 321.9±150.9 U/L.

Regarding the trial's secondary outcomes, Bowlus noted that only those patients treated with elafibranor achieved ALP normalization at 52 weeks (15% vs 0%, P=0.002), which is associated with improved survival in PBC.

Among the 66 patients with moderate-to-severe pruritus, Bowlus reported that while there was a trend for improvement in pruritus intensity favoring the elafibranor arm -- as measured by the Worst Itch Numeric Rating Scale (WI-NRS), a 1-10 scale where 10 represents the worse itch imaginable -- it did not reach statistical significance:

• 24-week scores: -1.60 with elafibranor vs -1.26 with placebo (-0.34 difference, 95% CI -1.49 to 0.80)
• 52-week scores: -1.93 vs -1.15, respectively (-0.78 difference, 95% CI -1.99 to 0.42)

Additionally, 52-week results appeared to favor the elafibranor-treated patients on both the itch domain of the PBC-40 quality-of-life questionnaire (least-squares mean difference of -2.3, 95% CI -4.0 to -0.7) and the total score of the 5-D itch scale (least-squares mean difference of -3.0, 95% CI -5.5 to -0.5).

During a Q&A session following the presentation, Jay Hoofnagle, MD, of the National Institutes of Health in Bethesda, Maryland, observed that the data on pruritus "was a wonderful demonstration of the placebo effect, which always affects us when we are assessing pruritus."

"You see it right away," he noted. "What you really need to measure is scratch, which is a sign rather than a symptom."

Capturing itch as a symptom is "quite complex and difficult," said Bowlus, and in the study involved not only the experience of itch but off-target effects in terms of symptoms. "The scratch is another symptom -- or activity, or sign -- that is hard to capture."

Regarding safety, adverse events (AEs) attributed to treatment occurred in a similar proportion of patients: 39% with elafibranor and 40% with placebo. Serious events of any kind occurred in 11% of each arm.

AEs reported more frequently the elafibranor arm were predominantly gastrointestinal in nature, including abdominal pain (11% vs 6% with placebo), diarrhea (11% vs 9%), nausea (11% vs 6%), and vomiting (11% vs 2%), but these were mostly mild or moderate intensity.

Elevated creatine phosphokinase levels and muscle injury were more common in patients receiving elafibranor than in those receiving placebo, resulting in discontinuation of elafibranor in four patients, though treatment discontinuation rates for AEs were similar overall (10% vs 9%, respectively).

Two deaths in the trial -- both in the elafibranor arm -- were not considered to be treatment related (postoperative complications after an elective surgery; and biliary sepsis and acute kidney injury in a patient with end-stage liver disease).

An open-label extension and , with event-free survival as its primary endpoint, will seek to capture the drug's effects on clinical outcomes.

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