Pooled analysis ASSUREs seladelpar role in PBC

Results of the phase III ASSURE study support seladelpar – a novel first-in-class delpar (selective peroxisome proliferator-activated receptor delta agonist) – for the treatment of primary biliary cholangitis (PBC).

“ASSURE is an ongoing study that includes patients who participated in the phase III RESPONSE study and prior seladelpar trials. [We aimed] to assess the pooled interim efficacy and safety for all patients in ASSURE for up to 3 years,” said the investigators, led by Dr Eric Lawitz from the Texas Liver Institute, University of Texas Health San Antonio in the US, at TLM 2024.

Key endpoints

“By month 30, seladelpar resulted in a durable and sustained biochemical response in 81 percent of patients, with an alkaline phosphatase (ALP) normalization rate of 41 percent and robust improvement in pruritus,” said Lawitz and colleagues.

A composite biochemical response (CBR) was defined as having an ALP level <1.67 x upper limit of normal, ≥15-percent reduction in ALP, and a normal total bilirubin (TB) level. The mean baseline ALP was 287.5 U/L. Of note, about three-quarters of evaluable patients met the CBR endpoint at months 12 and 24.

The ALP normalization rate also aligns with the month 12 and 24 results (38 percent for both timepoints). “The improvements in ALP levels were seen as early as month 1 and were maintained through month 30 … A lower ALP level is considered the main result that shows seladelpar is working,” the investigators noted.

In the pruritus numeric rating scale, the mean change from baseline at 6 months was −3.3 among 99 evaluable participants who had moderate-to-severe pruritus at baseline. [The Liver Meeting 2024, abstract 5044]

Other liver biochemistries

Among participants who had elevated alanine aminotransferase (ALT) at baseline, about two-thirds achieved ALT normalization at months 12 and 24. By month 30, this jumped to 90 percent.

At month 30 (n=37), mean ALT percent change from baseline was –29 percent, mean TB percent change from baseline (0.8 mg/dL) was –5 percent, mean gamma-glutamyl transferase percent change from baseline was –42 percent, while aspartate aminotransferase levels remained stable.

Safety overview

At 36 months, 63 patients had exposure-adjusted adverse events (AEs) per 100 patient-years. The corresponding numbers at months 12 and 24 were 86 and 70 patients.

No treatment-related serious AEs were reported. One fatal outcome due to autoimmune haemolytic anaemia was reported, but this was deemed unrelated to the study drug.

The most common AEs reported in the overall cohort were COVID-19, pruritus, and nausea. The incidences of exposure-adjusted liver-, muscle-, and renal-related AEs remained stable or decreased over 3 years of seladelpar use. Most of the AEs of interest were grade 1 or 2 in severity.

“Seladelpar continues to appear safe and well tolerated, with no new safety signals or changes in the frequency of AEs with up to 3 years of exposure,” the investigators noted.

Accelerated approval

This open-label trial included patients with PBC who rolled over from RESPONSE or participated in legacy seladelpar trials* (n=337; mean age 58.1 years, 94 percent women). [N Engl J Med 2024;390:783-794; Hepatology 2023;78:397-415; J Hepatol 2022;77:353-364; Aliment Pharmacol Ther 2024;59:186-200; https://clinicaltrials.gov/study/NCT03301506, https://clinicaltrials.gov/study/NCT04950764, accessed December 4, 2024]

Of the participants, 124 had up to or beyond 2 years of seladelpar exposure (n=34 reached 30 months on study; 90 had ≥24 months of exposure). They received seladelpar 10 mg daily. The parent studies required an inadequate response or intolerance to first-line ursodeoxycholic acid (UDCA).

In August 2024, the US FDA granted accelerated approval for seladelpar for PBC treatment in combination with UDCA in adults with insufficient response to UDCA, or as monotherapy for patients intolerant to UDCA. [https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217899s000lbl.pdf, accessed December 4, 2024]