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Reply to: “Seladelpar in patients with primary biliary cholangitis: Need for a closer look!”

Published:August 13, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.024

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      Linked Article

      To the Editor:
      We thank Drs. Mishra and Singh for their interest in our paper
      • Bowlus C.L.
      • Galambos M.R.
      • Aspinall R.J.
      • Hirschfield G.M.
      • Jones D.E.J.
      • Dorffel Y.
      • et al.
      A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.
      in which seladelpar, a potent and selective PPARδ agonist, demonstrated dose-dependent improvements in markers of cholestasis and inflammation
      • Bowlus C.L.
      • Galambos M.R.
      • Aspinall R.J.
      • Hirschfield G.M.
      • Jones D.E.J.
      • Dorffel Y.
      • et al.
      A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.
      and would like to clarify the 4 issues that they raised.
      • Mishra A.K.
      • Singh S.P.
      Seladelpar in patients with primary biliary cholangitis: need for a closer look!.
      First, we agree that non-alcoholic fatty liver disease (NAFLD) is a common condition in adults which is likely to be present in a subset of individuals with PBC
      • Hindi M.
      • Levy C.
      • Couto C.A.
      • Bejarano P.
      • Mendes F.
      Primary biliary cirrhosis is more severe in overweight patients.
      ,
      • Friedrich-Rust M.
      • Muller C.
      • Winckler A.
      • Kriener S.
      • Herrmann E.
      • Holtmeier J.
      • et al.
      Assessment of liver fibrosis and steatosis in PBC with FibroScan, MRI, MR-spectroscopy, and serum markers.
      and that a BMI >25 has been associated with steatosis or advanced fibrosis in PBC,
      • Hindi M.
      • Levy C.
      • Couto C.A.
      • Bejarano P.
      • Mendes F.
      Primary biliary cirrhosis is more severe in overweight patients.
      but we would also point out that this is not diagnostic of NAFLD and that BMI is only weakly correlated (0.46) with histological steatosis.
      • Friedrich-Rust M.
      • Muller C.
      • Winckler A.
      • Kriener S.
      • Herrmann E.
      • Holtmeier J.
      • et al.
      Assessment of liver fibrosis and steatosis in PBC with FibroScan, MRI, MR-spectroscopy, and serum markers.
      Teasing out a secondary benefit of seladelpar in patients with PBC and NAFLD would require more than simply monitoring liver stiffness and controlled-attenuation parameter values as suggested. Rather, it would require a study design similar to that done for seladelpar in patients with biopsy-proven non-alcoholic steatohepatitis
      • Harrison S.A.
      • Gunn N.T.
      • Khazanchi A.
      • Guy C.
      • Brunt E.
      • Moussa M.
      • et al.
      A 52-week multi-center double-blind randomized phase 2 study of seladelpar, a potent and selective peroxisome proliferator-activated receptor delta (PPAR-delta) agonist, in patients with nonalcoholic steatohepatitis (NASH).
      with the added requirement that participants have PBC with an incomplete biochemical response to ursodeoxycholic acid.
      Second, although the mean alkaline phosphatase (ALP) was slightly higher in the 5 mg compared to the 10 mg dose group, there were comparable numbers of individuals with cirrhosis in each group, 14 in the 5 mg and 11 in the 10 mg groups. The percent change in ALP from baseline to Week 12 for the 5 mg and 10 mg groups was −34.5% (n = 47) and −43.2 % (n = 51), respectively, in this study and was nearly identical to that of a subsequent phase III study
      • Hirschfield G.M.
      • Kowdley K.V.
      • Shiffman M.L.
      • Khazanchi A.
      • Zigmond E.
      • Lawitz E.J.
      • et al.
      ENHANCE: safety and efficacy of seladelpar in patients with primary biliary cholangitis—a phase 3 international, randomized, placebo-controlled study.
      where the corresponding change through Week 12 was −35.7% (n = 54) vs. −44.2% (n = 53) (p = 0.0013 for 5 mg vs. 10 mg). In this second study, the baseline ALP were well matched between groups at 290 and 291 U/L, respectively.
      Third, we are baffled by the assertion that seladelpar might induce pruritus. PPAR agonists have previously been noted to relieve pruritus and we refer Drs. Mishra and Singh to a recently published sub-analysis evaluating the impact of seladelpar on pruritus; seladelpar clearly improved itch (reduction in pruritus VAS of ≥20) in patients with significant baseline pruritus VAS (≥40).
      • Kremer A.E.
      • Mayo M.J.
      • Hirschfield G.
      • Levy C.
      • Bowlus C.L.
      • Jones D.E.
      • et al.
      Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis.
      The improvement in pruritus with seladelpar was confirmed in the subsequent placebo-controlled study.
      • Hirschfield G.M.
      • Kowdley K.V.
      • Shiffman M.L.
      • Khazanchi A.
      • Zigmond E.
      • Lawitz E.J.
      • et al.
      ENHANCE: safety and efficacy of seladelpar in patients with primary biliary cholangitis—a phase 3 international, randomized, placebo-controlled study.
      Finally, we agree that seladelpar might have utility as first-line therapy, but this would require a head-to-head comparison of seladelpar to UDCA. The currently accepted surrogate endpoints utilizing ALP and total bilirubin
      • Nevens F.
      • Andreone P.
      • Mazzella G.
      • Strasser S.I.
      • Bowlus C.
      • Invernizzi P.
      • et al.
      A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
      have been developed in UDCA-treated patients and have not been validated in UDCA-naïve patients in a contemporary setting. The validity of these surrogates would require further justification and/or evidence of improvement in clinical outcomes.

      Financial support

      Funding for the referenced study and manuscript was provided by CymaBay Therapeutics, which had a role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Cymabay Therapeutics had a role in the writing of this response and the decision to submit the response for publication.

      Authors' contributions

      Drafting of the manuscript: CLB, CL, and GMH.

      Conflict of interest

      Christopher Bowlus has received grants from Arena Pharmaceuticals, Cara Therapeutics, Genfit, Genkyotex, and Novartis and grants and personal fees from CymaBay Therapeutics, Eli Lilly, Gilead, GlaxoSmithKline, and Intercept. Cynthia Levy has received grants from Genkyotex, Gilead, High Tide, Intercept, Novartis, and Zydus and grants and personal fees from Cara Therapeutics, CymaBay Therapeutics, Genfit, and GlaxoSmithKline. Gideon M. Hirschfield has received personal fees from CymaBay Therapeutics, Genfit, GlaxoSmithKline, HighTide, Intercept Pharma, Mirum, and Pliant.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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