Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

Abstract

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-μg dose groups ranged from -10.7 to -16.5 U l^-1 versus placebo (-7.8 U l^-1) and tropifexor 140- and 200-μg groups were -18.0 U l^-1 and -23.0 U l^-1, respectively, versus placebo (-8.3 U l^-1)) and % HFF (tropifexor 10-90-μg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-μg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.

Fig. 1. Patient disposition.

a, Parts A + B. b, Part C. The figure reports the primary reason for discontinuation. ^a1 patient discontinued due to AE (Table 2); however, the AE was not the ‘primary’ reason for discontinuation. ^b5 patients discontinued due to AEs (Table 2); however, only 4 patients reported AEs as the primary reason for discontinuation (CK increased (1), constipation (1), pruritus (1), T2DM (1)). ^cAST increased (1), back pain (1). ^dPruritus (3), AST increased (1), drug eruption (1). ^e9 patients had a total of 12 AEs leading to discontinuation: pruritus (4), abdominal pain (2), AST increased (1), blood ALP increased (1), breast pain (1), diarrhea (1), increased liver stiffness, (1) oral paresthesia (1). CK, creatine phosphokinase; FAS, full analysis set; TXR, tropifexor.

Fig. 2. Change in ALT and AST from baseline up to end-of-treatment.

a, ALT Parts A + B. b, ALT Part C. c, AST Parts A + B. d, AST Part C. *P < 0.05, **P < 0.01, ***P < 0.001 versus placebo. Data are presented as LS mean change (s.e.) with two-sided unadjusted P values from repeated measures ANCOVA.

Fig. 3. Change from baseline in HFF.

a, HFF Parts A + B. b, HFF Part C. c, Response rate for HFF reduction ≥30% Part C. ***P < 0.001 versus placebo. Data are presented as LS mean change (s.e.) with two-sided unadjusted P values from repeated measures ANCOVA (HFF, Part C) or ANCOVA (HFF, Parts A + B). Response rate was defined as % patients achieving HFF reduction of ≥30% and is presented as response rate with 95% CI.

Extended Data Fig. 1. Study design.

^aWhen ≥90% of the patients in Part A completed 8 weeks of treatment, an interim analysis was performed to allow for the DMC to recommend dose selection for Part B. ^bRandomization to Part B commenced after the DMC recommendation on dose selection. ^cRandomization into Part C began after completion of Part B randomization. DMC, data monitoring committee; EOS, end-of-study; EOT, end-of-treatment; qd, once daily; RND, randomization; TXR, tropifexor.

Extended Data Fig. 2. Mean change from baseline in LDL-C and HDL-C.

a, LDL-C, Parts A+B. b, HDL-C, Parts A+B. c, LDL-C, Part C. d, HDL-C, Part C. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TXR, tropifexor.

Extended Data Fig. 3. Change from baseline in body weight.

a, Body weight Parts A+B. b, Body weight Part C. *P<0.05, **P<0.01, ***P<0.001 versus placebo. Data are presented as LS mean change (SE) with two-sided unadjusted P values from repeated measures ANCOVA. ANCOVA, analysis of covariance; LS, least squares; SE, standard error; TXR, tropifexor.

Extended Data Fig. 4. Changes in GGT and ALP from baseline to end-of-treatment.

a, GGT, Parts A+B. b, GGT, Part C. c, ALP, Parts A+B. d, ALP, Part C. *P<0.05, **P<0.01, ***P<0.001 versus placebo. Data are presented as LS mean change (SE) with two-sided unadjusted P values from repeated measures ANCOVA. ALP, alkaline phosphatase; ANCOVA, analysis of covariance; GGT, gamma-glutamyl transferase; LS, least squares; SE, standard error; TXR, tropifexor.

Extended Data Fig. 5. Changes in histologic features (paired and unpaired biopsy evaluation) at week 48 (Part C).

a, At least one-point improvement in fibrosis (NASH CRN staging) with no worsening of NASH. b, NASH resolution (score-based definition^a) with no worsening of fibrosis (NASH CRN staging). c, NASH resolution (diagnostic category [pathologist’s assessment independent of NAS score]) with no worsening of fibrosis (NASH CRN staging). Data are presented as response rate with 95% CI. ^aLobular inflammation ≤1 AND hepatocyte ballooning=0 AND any value for steatosis (definition as per FDA/EMA). CI, confidence interval; CRN, clinical research network; M, total number of subjects in the treatment group with response variable defined; n, number of subjects who responded NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; PBO, placebo; TXR, tropifexor.

Extended Data Fig. 6. Proportion of patients in each NAS sub-score category at baseline and week 48 (paired biopsy evaluation).

M, the total number of subjects with a value for a specific categorical variable; n, number of subjects who are at the corresponding category; N, the total number of subjects in the treatment group; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; TXR, tropifexor.

Extended Data Fig. 7. Comparison of fibrosis changes (Figures 6a-6c) and liver fat reduction (Figures 6e-6f) from baseline to week 48 (Part C).

a, Fibrosis score from blinded paired read. b, qFibrosis presented by stage. c, qFibrosis as a continuous value. d, qSteatosis. e, HFF by MRI-PDFF. f, Correlation between the % change in qSteatosis and MRI-PDFF from baseline to week 48. P values for qSteatosis (figure 6d): versus placebo, from ANCOVA adjusted by baseline value, no multiplicity correction; P values for HFF (figure 6e) ***P<0.001 repeated measures ANCOVA model. ANCOVA, analysis of covariance; HFF, hepatic fat fraction; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; TXR, tropifexor.