Positive RESPONSE for seladelpar in patients with PBC

Presenter Gideon Hirschfield (University of Toronto, Ontario, Canada) told delegates at The Liver Meeting 2023, held in Boston, Massachusetts, USA, that “seladelpar at 10 mg daily leads to six out of 10 patients meeting a primary composite endpoint, one in four patients normalizing their alkaline phosphatase [ALP], a more than 40% drop in alkaline phosphatase, and a significant improvement in their pruritus without safety concerns.”

For the study, 128 patients were randomly assigned to treatment with seladelpar, a first-in-class potent and selective PPAR-delta agonist, at 10 mg/day, or placebo for 12 months.

The participants (94.8% women) had a mean age of 56.7 years and most (94.0%) were taking UDCA. Baseline ALP levels were at least 1.67 times the upper limit of normal (ULN; mean 314.4 U/L), total bilirubin levels were up to twice the ULN (mean 0.76 mg/dL). Significant moderate-to-severe pruritus was reported by 37% of patients, as indicated by a score of 4 or above on the Numerical Rating Scale (NRS).

At 12 months, 61.7% of patients receiving seladelpar achieved the composite primary responder endpoint of an ALP level below 1.67 times the ULN, a total bilirubin level at or below the ULN, and at least a 15% decrease in ALP. This was significantly more than the 20% of patients who received placebo.

Hirschfield highlighted that there was a significant 42.4% reduction in ALP with seladelpar, which equates to a mean decrease of 133.9 IU/L, whereas ALP fell by just 4.3% (16.9 IU/L) with placebo.

 A key secondary endpoint was ALP normalization, which occurred in 25% of patients in the seladelpar arm, compared with none of the patients in the placebo arm.

“This is important because studies from the global PBC group have shown that patients who normalize their ALP have the best outcome when living with PBC,” said the presenter.

Seladelpar also significantly improved serum markers of liver injury, including levels of alanine aminotransferase and gamma-glutamyl transferase, as well as changes in triglycerides and low-density lipoprotein cholesterol profiles.

Among the 45 patients in the seladelpar group with an NRS score of 4 or higher, treatment was associated with a significant 3.2-point reduction compared with a 1.7-point reduction among the 20 affected patients in the placebo group.

This significant improvement continued over the full 12 months, noted Hirschfield, and was mirrored in the overall population, for whom there was also a significant reduction in the pruritogenic cytokine interleukin-31 with seladelpar, compared with an increase with placebo. The seladelpar reductions in pruritus were also accompanied by improvements in itch and sleep disturbance,

The adverse event rate was comparable across the two treatment groups, at 86.7% among those taking seladelpar and 84.6% among those given placebo, with no significant differences in muscle-related or liver-related adverse events (AEs).

There were no treatment-related AEsof grade 3 or above, no serious treatment-related AEs, and no deaths.

Indeed, Hirschfield pointed out that “96% of eligible patients completing treatment agreed to enter the open-label safety study.”