In the phase IIb/III EPICS-III study, the dual PPAR-α/γ agonist saroglitazar improves biochemical response (BCR) rates among individuals with primary biliary cholangitis (PBC) who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA).
Nearly 57 percent of participants treated with saroglitazar achieved the primary endpoint of BCR at week (W)52; only 9.8 percent did so in the placebo group (treatment difference, 48 percent; p<0.001). This pattern was also observed when stratifying by baseline alkaline phosphatase (ALP) levels (≤3× ULN: 83.1 percent vs 14.7 percent; >3× ULN: 18.7 percent vs 0 percent). [EASL 2026, abstract LBO-001]
“The response was rapid and early (37.2 percent at W2) and was sustained through W52,” said Dr Raj VuppaLanchi from the Indiana University School of Medicine, Indianapolis, Indiana, US, at EASL 2026.
The treatment effect was also consistent across most clinically relevant subgroups.
There was a sustained and substantial decline in ALP with saroglitazar compared with placebo through W52 (least squares mean [LSM] percent change from baseline –33.5 percent vs 6.5 percent; p<0.001), which was also evident as early as W2.
Eight percent of saroglitazar-treated patients achieved ALP normalization; none did with placebo (p=0.016).
Other parameters
W52 also saw greater LSM changes from baseline with saroglitazar than with placebo in liver biochemistries, such as ALT (–6.9 vs 4.4; p=0.043) and GGT (–47.8 vs 22.3; p=0.01); AST and total bilirubin levels were stable. A similar pattern was observed for lipid parameters, such as LDL-C (–15.1 vs 0.6 mg/dL; p<0.001), non–HDL-C (–20.9 vs –2.2 mg/dL; p<0.001), triglycerides (–25.2 vs –7.5 mg/dL; p=0.003), and VLDL-C (–5.1 vs –1.7 mg/dL; p=0.005).
Among participants with moderate-to-severe itch (baseline 5-D ≥12), the LSMs for the 5-D Itch total score decreased from baseline to W24 with placebo (from 16.6 to 14.5), more so with saroglitazar (from 16.7 to 11.1). The W24 between-group differences yielded a p-value of 0.009.
Safety profile
The saroglitazar group had a lower rate of serious treatment-emergent adverse events (TEAEs) than the placebo group (6.3 percent vs 11.1 percent). The most common TEAEs with saroglitazar were pruritus (22.5 percent) and headache (15.3 percent).
Moreover, in the saroglitazar group, one patient had elevations in creatine phosphokinase >3× ULN, and there was one death related to metastatic lung cancer but unrelated to the study drug, VuppaLanchi said.
Compared with the placebo group, the saroglitazar group had slightly more patients with AEs of special interest, such as fractures (n=4 vs 1) and weight gain ≥5 kg (n=23 vs 12), as well as discontinuations due to TEAEs (n=5 vs 2).
“Nonetheless, none met the Hy’s law criteria nor were there any drug-induced liver injuries from saroglitazar,” VuppaLanchi said. Four patients in the saroglitazar group had potential hepatic events, but none were deemed related to the study drug.
One saroglitazar-treated patient had a serious AE of variceal haemorrhage, which was adjudicated as disease progression and unrelated to the study drug. Of note, this patient had known varices and cirrhosis at baseline.
Novel PPAR therapy
“Despite standard first-line treatment with UDCA, many PBC patients do not achieve adequate biochemical control. PPAR agonists have recently emerged as second-line treatment options,” said VuppaLanchi.
In the phase IIb dose-finding portion of the study, 37 participants were randomized 1:1:1 to saroglitazar magnesium 1 or 2 mg or placebo for 16 weeks. Based on its results, saroglitazar 1 mg was selected for phase III, which randomized 148 patients (median age at screening 56 years, ~90 percent women) 2:1 to saroglitazar or placebo for 52 weeks.
VuppaLanchi noted that the saroglitazar group generally had higher baseline ALP and liver biochemistries than the placebo group.
“[Taken together,] saroglitazar represents a novel and efficacious PPAR therapy in individuals with PBC who had an inadequate response or intolerance to UDCA,” VuppaLanchi concluded.