Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis

Abstract

Background & aims: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response.

Methods: We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve.

Results: The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001).

Conclusions: In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.

Keywords: FLINT Trial; FXR Agonist; NAFLD; OCA.

Conflict of interest statement

Conflict of Interest Statements:

Dr. Loomba serves on the steering committee of the REGENERATE trial and was the co-chair of the FLINT trial protocol writing committee. Dr. Loomba has received research funding from Intercept Pharmaceutical.

Dr. Sanyal reports no conflicts of interest for this project. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect. He has served as a consultant to AbbVie, Astra Zeneca, Nitto Denko, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Fibrogen, Jannsen, Gilead, Boehringer, Lilly, Zafgen, Novartis, Pfizer, Immuron, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Novo Nordisk, Affimune, Chemomab, Nordic Bioscience and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Novartis. He receives royalties from Elsevier and UptoDate.

Dr. Kowdley has ongoing (or in the last 12 months) had consulting activities, advisory arrangements, speakers’ bureau and research grants from Gilead and Intercept Pharmaceuticals. He has also had advisory arrangements from Novartis and received research grants from GSK, Genefit, and Novartis.

Dr. Terrault has served on advisory boards for Intercept Pharmaceuticals.

Dr. Chalasani has ongoing consulting activities (or had in the preceding 12 months) with NuSirt, Abbvie, Eli Lilly, Afimmune (DS Biopharma), Tobira (Allergan), Madrigal, Shire, Cempra, Ardelyx, Axovant, Immuran and Amarin. These consulting activities are generally in the areas of nonalcoholic fatty liver disease and drug hepatotoxicity. Dr. Chalasani receives research grant support from Intercept, Lilly, Gilead, Galectin Therapeutics and Cumberland where his institution receives the funding. Over the last decade, Dr. Chalasani has served as a paid consultant to more than 30 pharmaceutical companies and these outside activities have regularly been disclosed to his institutional authorities.

Dr. Abdelmalek has received grant / research funding from Intercept for studies in NASH. Dr. Abdelmalek has ongoing (or in the last 12 month) had advisory or consulting activities for Immuron, BMS, NGM Bio, Madrigal, TaiwanJ, Pfizer, Lexicon, and Medimmune. Dr. Abdelmalek is on the speaker’s bureau for Alexion. Her institution has received grant funding for NASH research from Conatus, Intercept, Allergan, BMS, NGM Bio, TaiwanJ, Madrigal, Shire, Immuron, Galactin, Genfit, Enanta, Beohringer-Ingelheim, and Gilead. Dr. Abdelmalek receives royalties from UptoDate.

Dr. McCullough has nothing to disclose.

Reshma Shringarpure, Lois Lee, Alexander Liberman, David Shapiro are employees and shareholders of Intercept Pharmaceuticals, Inc.

Beatrice Ferguson and Jianfen Chen were previously employees of Intercept Pharmaceuticals, Inc. and are currently shareholders of Intercept Pharmaceuticals Inc.

Dr. Neuschwander-Tetri has advised/consulted for Galmed, Zafgen, Receptos, Pfizer, Allergan, MedImmune/AstraZeneca, ConSynance, Tobira, Karos, Afimmune, NuSirt, Arrowhead, Reset, and Intercept Pharmaceuticals, Inc.

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Forest Plot of Predictors of Histologic Response.

Plot shows the odds ratio and 95% CI for each of the selected predictors of responses, if the odds ratio is >1, the predictor is associated with higher odds of histological response. Significance of each of the selected predictors was assessed using a Wald Chi-Square test.

Figure 2.. Receiver Operator Characteristic Curves

The ROC curve for the overall population (n=200) is shown in red; the ROC curve for patients receiving OCA (n=102) is shown in purple and the ROC curve for patients receiving Placebo (n=98) is shown in black. The model was significant when applied to the overall population as well as each of the treatment groups (p

Figure 3.. Scatterplot of Model Predictions.

Scatterplot shows the probability of histologic response and accuracy of each prediction for all patients assessed in this analysis.