Predictors of Improvement in NAFLD Activity Score on Placebo: A Secondary Analysis of the Flint Trial

ORAL PRESENTATIONS Results: NDI-010976 was well tolerated. Overnight infusion of 13Cacetate led to incorporation of the 13C label into the hepatic pool of acetyl-CoA. Periodic oral fructose administration over a 10 hr period stimulated hepatic DNL an average of 31 ± 7% over baseline in placebo treated subjects. Assessment of the available data demonstrated that all subjects administered NDI-010976 at doses of 20, 50, and 200 mg had substantial inhibition of de novo lipogenesis (mean inhibition 71%, 87%, and 98%, respectively). Following a single dose of 50 mg NDI-010976, all subjects had greater than 70% inhibition of DNL as determined by baseline normalized AUC over the 10 hr period as compared to the matched placebo period. Moreover, all subjects administered 200 mg NDI-010976 had complete, or near complete, inhibition of DNL. Conclusions: This clinical pharmacodynamic study demonstrates that ACC target engagement by NDI-010976 resulted in substantial dose-dependent inhibition of fractional de novo lipogenesis in the liver of adult male subjects who are overweight and/or obese, but otherwise healthy. Therefore, NDI-010976 has the potential to contribute considerable value to the treatment algorithm of NASH. PS109 PREDICTORS OF IMPROVEMENT IN NAFLD ACTIVITY SCORE ON PLACEBO: A SECONDARY ANALYSIS OF THE FLINT TRIAL R. Loomba1, A.J. Sanyal2, K.V. Kowdley3, N. Terrault4, N.P. Chalasani5, M.F. Abdelmalek6, A.J. McCullough7, B. Ferguson8, L. Lee8, R. Shringarpure8, D. Shapiro8, B.A. Neuschwander-Tetri9. 1University of California, San Diego, La Jolla; 2Virginia Commonwealth University, Richmond; 3Swedish Medical Center, Seattle; 4University of California, San Francisco, San Francisco; 5Indiana University, Indianapolis; 6Duke University, Durham; 7Cleveland Clinic, Cleveland; 8Intercept Pharmaceuticals, Inc., San Diego; 9Saint Louis University Health Sciences Center, St. Louis, United States E-mail: [email protected] Background and Aims: The FLINT Trial showed that obeticholic acid (OCA) led to significantly higher rates of histological response (defined as an improvement in NAFLD activity score by [NAS] ≥2 with no worsening of fibrosis) compared to placebo (PBO). However, some patients in the PBO group also met the histological response criteria after 72 weeks of treatment. The aim of this post-hoc analysis of the FLINT trial was to identify predictors of histological response after 72 weeks of receiving PBO. Methods: A logistic regression model with stepwise selection procedure was performed to identify potential predictors of histological response after 72 weeks of receiving PBO. Model selection was based on Akaike information criterion (AIC) and Bayesian information criterion (BIC). All patients included in the analysis had biopsies at baseline (BL) and 72 weeks. Patient’s clinical parameters collected at BL for demographics, histology, liver, and serum biochemistry as well as the changes in those parameters over the course of the trial at weeks 12, 24, and 36 were evaluated and used to build a model in PBO-treated patients to predict histological

response. The model was cross-validated by jackknife method and area under the receiver operating characteristic curve (AUROC) with associated 95% confidence intervals. Results: Among the 98 patients who received PBO for 72 weeks, 23% had a histological response. This predictive model of histological response on PBO showed that a higher lobular inflammation at BL, a lower BMI at BL, a greater decrease in ALT at week 24, a greater decrease in ALP at week 36, a greater decrease in cholesterol at week 24, and a greater increase in platelet count at week 24 were associated with an AUROC of 0.88 (95% CI; 0.81–0.95, p-value <0.001); histological response in the PBO treatment group (Table). All of the predictors included in the model were significant ( p < 0.05) with an exception of BMI at BL. Lobular inflammation at BL had the highest odds ratio and was the most significant predictor of response ( p < 0.001) in patients who received PBO. Conclusions: Baseline characteristics and changes in clinical parameters may predict histological response in adults with NASH. Improvements were not simply mediated by weight loss. These data have important implications for future clinical trials. PS110 LEAN-NON-ALCOHOLIC FATTY LIVER DISEASE WITH CENTRAL VISCERAL OBESITY IDENTIFIES PATIENTS WITH MORE SEVERE DISEASE R. Lombardi1, L. Mensi1, G. Pisano1, P. Dongiovanni1, C. Bertelli1, E. Fatta1, L. Valenti1, S. Fargion1, A.L. Fracanzani1. 1Unit of Internal Medicine, Department of Pathophysiology and Transplantation Unit, Ca’ Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Milan, Italy E-mail: [email protected] Background and Aims: Obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD), however a proportion of patients develop NAFLD despite having a normal body mass index (BMI), this condition is referred to as lean or non-obese NAFLD. To evaluate the metabolic, cardiovascular and histological features of lean-NAFLD we studied 323 consecutive patients with biopsy proven NAFLD. Methods: Biochemical parameters, carotid atherosclerotic lesions by ultrasonography, PNPLA3 genotyping and liver histology were recorded. Subjects were divided according to BMI <25 (defined as lean-NAFLD) or ≥25 kg/m2, and to waist circumference, surrogate marker of visceral obesity (< or ≥88 cm (for female) and < or ≥102 cm (for male)). Results: Lean-NAFLD (60 patients, 14 female, mean age 49 ± 11) had significantly lower prevalence of hypertension (20% vs. 42%, p = .001), diabetes (8% vs. 25%, p = .003), metabolic syndrome (13% vs. 42%, p = .002) than overweight/obese NAFLD (263 patients, 57 female, mean age 51 ± 11), while lipid parameters did not differ. Carotid intima-media thickness (0.7 ± 0.1 vs. 0.8 ± 0.1, p = .0001), carotid plaques (13% vs. 33%, p = .007), cardiovascular risk (4.1 ± 6.6, p = .007, prevalence of NASH (37% vs. 62%, p = .0005) and of significant fibrosis (> or equal F2) (4% vs. 13%, p = 0.02) were significantly lower in

Table (abstract: PS109): Clinical Model for Predictors of Histological Response in the PBO Group Performance Characteristics Predictors

Odds Ratio

AUROC

Sensitivity

Specificity

PPV

NPV

-Higher Lobular Inflammation at BL -Lower BMI at BL (kg/m2) -Decrease in ALT at 24 wks (20 U/L) -Decrease in ALP at 36 wks (10 U/L) -Decrease in Cholesterol at 24 wks (10 mg/dL) -Increase in Platelet at 24 wks (109/L)

9.02 0.89 1.84 2.58 1.36 1.03

0.88 (95% CI: 0.81–0.95) Cut Point: 0.37

72.7%

90.3%

69.6%

91.5%

Histological response was defined as an improvement in NAS by ≥2 with no worsening of fibrosis ALP = alkaline phosphatase; ALT = alanine aminotransferase; AUROC = area under the receiver operator curve; BL = baseline; BMI = body mass index; CI = confidence interval; NAS = NAFLD activity score; NPV = negative predictive value; PPV = positive predictive value; wks = weeks Journal of Hepatology 2016 vol. 64 | S183–S212

S191