Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.
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Hirschfield Gideon M, Shiffman Mitchell L, Gulamhusein Aliya, Kowdley Kris V, Vierling John M, Levy Cynthia, Kremer Andreas E, Zigmond Ehud, Andreone Pietro, Gordon Stuart C, Bowlus Christopher L, Lawitz Eric J, Aspinall Richard J, Pratt Daniel S, Raikhelson Karina, Gonzalez-Huezo Maria S, Heneghan Michael A, Jeong Sook-Hyang, Ladrón de Guevara Alma L, Mayo Marlyn J, Dalekos George N, Drenth Joost P H, Janczewska Ewa, Leggett Barbara A, Nevens Frederik, Vargas Victor, Zuckerman Eli, Corpechot Christophe, Fassio Eduardo, Hinrichsen Holger, Invernizzi Pietro, Trivedi Palak J, Forman Lisa, Jones David E J, Ryder Stephen D, Swain Mark G, Steinberg Alexandra, Boudes Pol F, Choi Yun-Jung, McWherter Charles A, ENHANCE Study Group*
Аннотация
APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.
CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.