Treatment efficacy and safety of low dose seladelpar, a selective PPAR-δ agonist, in patients with primary biliary cholangitis: Twelve-week interim analysis of an international, randomized, dose ranging, phase 2 study.

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Background. In a previous phase 2 study (NCT02609048), Seladelpar, a selective PPAR-δ agonist, demonstrated overt potent anti-cholestatic activity at doses of 50 and 200 mg/day in primary biliary cholangitis (PBC) patients with an inadequate response to ursodeoxycholic acid (UDCA). However, the study was terminated because of transaminase elevation. This study (NCT02955602) evaluates whether the efficacy of lower doses of Seladelpar can be retained without causing transaminase elevation. Methods. This open-label international study enrolls patients with PBC and an inadequate response to UDCA (alkaline phosphatase -AP- ≥1.67 upper limit of normal), or an intolerance of UDCA. Patients are randomized to Seladelpar 5 mg or 10 mg per day for 26 weeks. A pre-specified interim analysis of safety and efficacy was conducted. The primary outcome of efficacy is the % change from baseline in AP. Secondary outcomes include absolute changes in AP, AP responder analyses; changes in other markers of cholestasis (γ-glutamyl-transpeptidase -GGT-, total bilirubin), alanine amino transferase (ALT), LDL-Cholesterol, C-reactive protein (hs-CRP); and pruritus evaluated with a visual analog scale (VAS) and specific questionnaires. Safety analyses include discontinuation for safety, evaluation of adverse events, and routine laboratory markers. Results. There were no serious adverse events and no safety concerns with transaminase elevation. One patient entered the study with intense pruritus and discontinued Seladelpar 10 mg after 5 days for an increase in pruritus, possibly related to PBC, ciprofloxacin, or Seladelpar. In both groups the median VAS decreased between day 1 and week 12 (from 8 to 3 and from 25 to 6, in the 5 and 10 mg groups, respectively). At baseline, mean (SD) AP were 356 (180) and 260 (60) U/L and mean (SD) ALT were 39 (19) and 52 (27) U/L in the 5 and 10 mg groups, respectively. At 12 weeks, AP fell by 39% and 45% respectively at 5 and 10mg, corresponding to a mean (SD) absolute change of -146 (96) and -107 (33) U/L at 5 and 10 mg, respectively, and 18% and 45% of patients had a normal AP on 5 and 10 mg, respectively. The mean or median∗ % change from baseline to 12 weeks for efficacy parameters are tabulated below. Conclusion. In an interim 12-week analysis, at doses of 5 mg and 10 mg/day, Seladelpar appeared well tolerated and safe, was not associated with pruritus, and retained highly potent anti-cholestatic effects.





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