A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

[Histological lesions in the graft in patients with long-term survival after transplantation. Are protocol biopsies necessary?]. / Lesiones histológicas en el injerto en pacientes con supervivencia prolongada tras el trasplante hepático: ¿son necesarias biopsias de protocolo?

The main lesions found in long-term liver grafts are recurrence of underlying liver disease and the development of de novo diseases or heterogeneous lesions of unknown etiology. In a not insignificant percentage of patients, the results of laboratory tests are normal and these lesions are only detected by liver biopsy. Diagnosis of these lesions is essential since they can affect patient and graft prognosis and may require changes in immunosuppressive therapy or the introduction of new drugs to treat specific diseases. Moreover, some patients with normally functioning liver grafts could benefit from minimization of immunosuppressive therapy. Currently, the performance of protocol biopsies cannot be recommended. However, given the high prevalence of these lesions, grafts should be closely monitored. Transient elastrography could play a role in the selection of patients who might benefit from a liver biopsy.

Lesiones histológicas en el injerto en pacientes con supervivencia prolongada tras el trasplante hepático: ¿son necesarias biopsias de protocolo? / Histological lesions in the graft in patients with long-term survival after transplantation. are protocol biopsies necessary?

La recidiva de la enfermedad hepática de base, la aparición de enfermedades de novo o la aparición de otras lesiones heterogéneas de etiología desconocida son las principales lesiones se encuentran en injertos hepáticos a largo plazo. En un porcentaje no despreciable de casos la analítica es normal y estas lesiones solo se detectan mediante biopsia hepática. Diagnosticarlas es fundamental ya que pueden afectar al pronóstico del paciente y del injerto, condicionar la necesidad de realizar cambios en el tratamiento inmunosupresor o introducir nuevos medicamentos para tratar enfermedades específicas. Además, algunos pacientes seleccionados con injertos hepáticos normo-funcionantes podrían beneficiarse de minimizar la inmunosupresión. Actualmente no se puede recomendarla realización de biopsias de protocolo, pero dada la elevada prevalencia de estas lesiones se debe realizar un seguimiento estrecho del injerto. La elastografía de transición podría tener un papel en la selección de pacientes que se beneficien de la realización de una biopsia hepática (AU)

The main lesions found in long-term liver grafts are recurrence of underlying liver disease and the development of de novo diseases or heterogeneous lesions of unknown etiology. In a not insignificant percentage of patients, the results of laboratory tests are normal and these lesions are only detected by liver biopsy. Diagnosis of these lesions is essential since they can affect patient and graft prognosis and may require changes in immunosuppressive therapy or the introduction of new drugs to treat specific diseases. Moreover, some patients with normally functioning liver grafts could (..) (AU)