Ratziu, Vlad

Background and Aims: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. Approach and Results: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: −21%, TXR140; −16%, TXR140 + CVC; −13%, TXR90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR140, −2.5 kg; TXR140 + CVC, −1.7 kg; TXR90 + CVC, −1.0 kg; and CVC, −0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC, and TXR90 + CVC groups, respectively. Conclusions: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Abstract Background and Aims The NASH Clinical Research Network histologic scoring system, the gold‐standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). Approach and Results Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80–0.85) and interrater (0.60–0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68–0.79), including those extending scores from 0–2 to 0–4. Steatosis measures (interrater ICCs, 0.72–0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory‐Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70–0.87. Conclusions After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.