P47 Efficacy and safety of seladelpar as monotherapy in patients with primary biliary cholangitis and intolerance to ursodeoxycholic acid

<h3></h3> Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for the treatment of primary biliary cholangitis (PBC) including pruritus in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. In two Phase 3, placebo-controlled studies (ENHANCE [NCT03602560], RESPONSE [NCT04620733]), seladelpar led to a significantly higher rate of composite biochemical response (CBR; alkaline phosphatase [ALP] &lt;1.67 × the upper limit of normal [ULN], ≥15% decrease in ALP, and total bilirubin [TB] ≤ULN) and ALP normalization compared with placebo. Here, we present pooled efficacy and safety data on patients with UDCA intolerance receiving seladelpar as monotherapy in these studies. Patients with PBC who had an inadequate response or intolerance to UDCA, ALP ≥1.67 × ULN, and TB ≤2 × ULN were randomized in 2 trials: ENHANCE (1:1:1 to daily placebo, seladelpar 5 mg, or seladelpar 10 mg for 52 weeks; study terminated early with endpoints amended to month 3) and RESPONSE (2:1 to daily seladelpar 10 mg or placebo for 52 weeks). Patients intolerant to UDCA were eligible if their last dose was &gt;3 months before study entry. This post hoc analysis presents pooled efficacy (CBR, ALP normalization, and other liver biochemistries) and safety data for seladelpar 10 mg monotherapy vs placebo from ENHANCE and RESPONSE through month 3. In total, 369 patients were randomized to seladelpar 10 mg or placebo across both studies, 16 of whom received seladelpar monotherapy and 6 received placebo without UDCA. Mean baseline ALP was similar between monotherapy patients receiving seladelpar vs placebo (380 U/L vs 397 U/L). At month 3, 8/13 patients (62%) receiving seladelpar monotherapy demonstrated a CBR vs 1/6 patients (17%) receiving placebo, and 3/13 patients (23%) on seladelpar achieved normalized ALP vs 0/6 patients on placebo. Mean percent change from baseline in ALP at month 3 was −46% with seladelpar vs −2% with placebo. At month 3, 9/16 patients (56%) on seladelpar monotherapy experienced an adverse event (AE) vs 5/6 patients (83%) on placebo. No serious AEs and no discontinuations due to AEs occurred through month 3 with seladelpar monotherapy. Efficacy and safety results for seladelpar monotherapy were similar to results previously observed for seladelpar combined with UDCA. Seladelpar 10 mg monotherapy led to notable CBR rates and ALP reductions. Seladelpar monotherapy was well tolerated and had a similar safety profile compared with placebo.