Implementation of a National Liver Review Board for exception requests in the United States: A 2-year monitoring report.

The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-stage Liver Disease does not effectively represent their urgency or need for a transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to 1 National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first 2 years after implementation of the NLRB and acuity circle-based distribution in the United States. We compared initial and extension exception request forms submitted from May 13, 2017 to May 13, 2019 (prepolicy or RRB era) to the period from February 4, 2020 to February 3, 2022 (postpolicy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable postpolicy highlights include (1) an increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) a decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable. Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplants.

Long-term outcomes (beyond 5 years) of liver transplant recipients-A transatlantic multicenter study.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.

Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Belatacept Treatment of Recurrent Late-onset T Cell-mediated Rejection/Antibody-mediated Rejection With De Novo Donor-specific Antibodies in a Liver Transplant Patient.

T cell-mediated rejection that appears and persists late after transplantation is often associated with development of de novo donor-specific antibodies. Treatment of this condition often presents a conundrum because of the uncertainty regarding the trade-off between immunosuppression-related toxicities/complications and restoration of allograft function and structure. Methods: Herein, we report an illustrative case of a young 20-y-old otherwise healthy woman who underwent liver replacement for Alagille's syndrome from an ABO-compatible, 6 antigen-mismatched crossmatch-negative 24-y-old man. Although triple baseline immunosuppression was used (tacrolimus, mycophenolate mofetil, and prednisone), she developed rejection 3 d after liver replacement. Despite verified continual immunosuppression compliance, 1.5 y after liver replacement she experienced 6 more rejection episodes over the following 18 mo and development of de novo donor-specific antibody. Results: Treatment with belatacept began 3.5 y after transplantation, normalizing her liver tests with no further rejections. A biopsy obtained 6 y after transplantation (postoperative day 2221) was normal, appearing without inflammation or residual fibrosis. Conclusions: Belatacept may be a useful treatment approach in this setting.

Prediction of long-term morbidity and mortality after liver transplantation using two-dimensional shear wave elastography compared with liver biopsy.

The role of noninvasive liver disease assessment by two-dimensional shear wave elastography (2D-SWE) to diagnose fibrosis is well described in patients with chronic liver disease. However, its role in prognosis, especially after liver transplantation (LT) has not been adequately examined. We hypothesized that elevated liver stiffness measurement (LSM) as measured by 2D-SWE after LT predicts future morbidity and mortality independent of fibrosis by liver biopsy. In a prospective cohort study, consecutive LT recipients underwent concomitant protocol 2D-SWE and protocol liver biopsy (2012-2014), with the assessor blinded to biopsy findings. We examined the baseline correlation of LSM with fibrosis stage and the association between elevated LSM and the development of subsequent clinical outcomes and all-cause mortality. A total of 187 LT recipients (median age 58 years, 38.5% women, median body mass index 26.5 kg/m2 , 55.1% hepatitis C virus, 17.6% nonalcoholic steatohepatitis/cryptogenic) were examined. Median time between LT and biopsy/2D-SWE assessment was 4.0 years, and the median follow-up time after LSM determination was 3.5 years. Median LSM was 9 kPa (8 kPa [F0/F1], 11.5 kPa [F2], 12 kPa [F3/F4]). There was a positive correlation between LSM and fibrosis stage (rs  = 0.41; p < 0.001). LSM ≥11 kPa was associated with lower survival within 3 years (84.8 vs. 93.7%; p = 0.04). After adjusting for age, sex, and fibrosis stage, LSM ≥11 kPa was independently associated with mortality (hazard ratio, 2.45; 95% confidence interval, 1.08-5.60). Elevated LSM by 2D-SWE is associated with increased mortality after LT independent of hepatic fibrosis. Given the overall decrease in the use of liver biopsy in the current era, 2D-SWE may serve as a novel noninvasive prognostic tool to predict relevant outcomes late after LT.

The Effect of Acuity Circles on Deceased Donor Transplant and Offer Rates Across Model for End-Stage Liver Disease Scores and Exception Statuses.

Acuity circles (AC), the new liver allocation system, was implemented on February 4, 2020. Difference-in-differences analyses estimated the effect of AC on adjusted deceased donor transplant and offer rates across Pediatric End-Stage Liver Disease (PELD) and Model for End-Stage Liver Disease (MELD) categories and types of exception statuses. The offer rates were the number of first offers, top 5 offers, and top 10 offers on the match run per person-year. Each analysis adjusted for candidate characteristics and only used active candidate time on the waiting list. The before-AC period was February 4, 2019, to February 3, 2020, and the after-AC period was February 4, 2020, to February 3, 2021. Candidates with PELD/MELD scores 29 to 32 and PELD/MELD scores 33 to 36 had higher transplant rates than candidates with PELD/MELD scores 15 to 28 after AC compared with before AC (transplant rate ratios: PELD/MELD scores 29-32, 2.34 3.324.71 ; PELD/MELD scores 33-36, 1.70 2.513.71 ). Candidates with PELD/MELD scores 29 or higher had higher offer rates than candidates with PELD/MELD scores 15 to 28, and candidates with PELD/MELD scores 29 to 32 had the largest difference (offer rate ratios [ORR]: first offers, 2.77 3.955.63 ; top 5 offers, 3.90 4.394.95 ; top 10 offers, 4.85 5.305.80 ). Candidates with exceptions had lower offer rates than candidates without exceptions for offers in the top 5 (ORR: hepatocellular carcinoma [HCC], 0.68 0.770.88 ; non-HCC, 0.73 0.810.89 ) and top 10 (ORR: HCC, 0.59 0.650.71 ; non-HCC, 0.69 0.750.81 ). Recipients with PELD/MELD scores 15 to 28 and an HCC exception received a larger proportion of donation after circulatory death (DCD) donors after AC than before AC, although the differences in the liver donor risk index were comparatively small. Thus, candidates with PELD/MELD scores 29 to 34 and no exceptions had better access to transplant after AC, and donor quality did not notably change beyond the proportion of DCD donors.

Cost Analysis of Liver Acquisition Fees Before and After Acuity Circle Policy Implementation.

Importance: Acuity circles (AC) liver allocation policy was implemented to eliminate donor service area geographic boundaries from liver allocation and to decrease variability in median Model of End-stage Liver Disease (MELD) score at transplant and wait list mortality. However, the broader sharing of organs was also associated with more flights for organ procurements and higher costs associated with the increase in flights. Objective: To determine whether the costs associated with liver acquisition changed after the implementation of AC allocation. Design, Setting, and Participants: This single-center cost comparison study analyzed fees associated with organ acquisition before and after AC allocation implementation. The cost data were collected from a single transplant institute with 2 liver transplant centers, located 30 miles apart, in different donation service areas. Cost, recipient, and transportation data for all cases that included fees associated with liver acquisition from July 1, 2019, to October 31, 2020, were collected. Exposures: Primary liver offer acceptance with associated organ procurement organization or charter flight fees. Main Outcomes and Measures: Specific fees (organ acquisition, surgeon, import, and charter flight fees) and total fees per donor were collected for all accepted liver donors with at least 1 associated fee during the study period. Results: Of 213 included donors, 171 were used for transplant; 90 of 171 (52.6%) were male, and the median (interquartile range) age of donors was 41.0 (30.0-52.8) years in the pre-AC period and 36.9 (24.0-48.8) years in the post-AC period. There was no significant difference in the post-AC compared with pre-AC period in median (range) MELD score (24 [8-40] vs 25 [6-40]; P = .27) or median (range) match run sequence (15 [1-3951] vs 10 [1-1138]; P = .31), nor in mean (SD) distance traveled (155.83 [157.00] vs 140.54 [144.33] nautical miles; P = .32) or percentage of donors requiring flights (58.5% [69 of 118] vs 56.8% [54 of 95]; P = .82). However, costs increased significantly in the post-AC period: total cost increased 16% per accepted donor (mean [SD] of $52 966 [13 278] vs $45 725 [9300]; P < .001) and 55% per declined donor (mean [SD] of $15 865 [3942] vs $10 217 [4853]; P < .001). Contributing factors included more than 2-fold increases in the proportions of donors incurring import fees (31.4% [37 of 118] vs 12.6% [12 of 95]; P = .002) and surgeon fees (19.5% [23 of 118] vs 9.5% [9 of 95]; P = .05), increased acquisition fees (10% increase; mean [SD] of $43 860 [3266] vs $39 980 [2236]; P < .001), and increased flight expenses (43% increase; mean [SD] of $12 904 [6066] vs $9049 [5140]; P = .002). Conclusions and Relevance: The unintended consequences of implementing broader sharing without addressing organ acquisition fees to account for increased importation between organ procurement organizations must be remedied to contain costs and ensure viability of transplant programs.

TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial.

BACKGROUND & AIMS: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States. METHODS: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment. RESULTS: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups. CONCLUSIONS: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

Estimating Glomerular Filtration Rate in Cirrhosis Using Creatinine-Based and Cystatin C-Based Equations: Systematic Review and Meta-Analysis.

Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual-organ transplantation. We performed a systematic review/meta-analysis to assess the performance of creatinine-based and cystatin C (CysC)-based eGFR equations compared with measured GFR (mGFR) in patients with cirrhosis. A total of 25 studies (n = 4565, 52.0 years, 37.0% women) comprising 18 equations met the inclusion criteria. In all GFR equations, the creatinine-based equations overestimated GFR (standardized mean difference, SMD, 0.51; 95% confidence interval [CI], 0.31-0.71) and CysC-based equations underestimated GFR (SMD, -0.3; 95% CI, -0.60 to -0.02). Equations based on both creatinine and CysC were the least biased (SMD, -0.14; 95% CI, -0.46 to 0.18). Chronic kidney disease-Epi-serum creatinine-CysC (CESC) was the least biased but had low precision and underestimated GFR by -3.6 mL/minute/1.73 m2 (95% CI, -17.4 to 10.3). All equations significantly overestimated GFR (+21.7 mL/minute/1.73 m2 ; 95% CI, 17.7-25.7) at GFR <60 mL/minute/1.73 m2 ; of these, chronic kidney disease-Epi-CysC (10.3 mL/minute/1.73 m2 ; 95% CI, 2.1-18.4) and GFR Assessment in Liver Disease (12.6 mL/minute/1.73 m2 ; 95% CI, 7.2-18.0) were the least biased followed by Royal Free Hospital (15 mL/minute/1.73 m2 ; 95% CI, 5.5-24.6) and Modification of Diet in Renal Disease 6 (15.7 mL/minute/1.73 m2 ; 95% CI, 10.6-20.8); however, there was an overlap in the precision of estimates, and the studies were limited. In ascites, overestimation of GFR was common (+8.3 mL/minute/1.73 m2 ; 95% CI, -3.1 to 19.7). However, overestimation of GFR by 10 to 20 mL/minute/1.73m2 is common in patients with cirrhosis with most equations in ascites and/or kidney dysfunction. A tailored approach is required especially for decisions regarding dual-organ transplantation.

Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). METHODS: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. RESULTS: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.

Prospective Multicenter Study of Early Antiviral Therapy in Liver and Kidney Transplant Recipients of HCV-Viremic Donors.

BACKGROUND AND AIMS: Organs from hepatitis C virus (HCV)-viremic donors have been used in HCV-uninfected recipients (D+/R-), but the optimal treatment approach has not been defined. We evaluated the kinetics of HCV infection following transplant in D+/R- kidney-transplant (KT) and liver-transplant (LT) recipients when a preemptive antiviral strategy was used. APPROACH AND RESULTS: Six US transplant programs prospectively treated D+/R- primary LT and KT recipients with sofosbuvir-velpastasvir for 12 weeks starting once viremia was confirmed following transplant and the patients were judged to be clinically stable, including estimated glomerular filtration rate >30 mL/min. Primary endpoints were sustained virologic response at 12 weeks following transplant and safety (assessed by proportion of treatment-related adverse and serious adverse events). Of the 24 patients transplanted (13 liver, of whom 2 had prior-treated HCV infection; 11 kidney), 23 became viremic after transplant. The median (interquartile range) time from transplant to start of antiviral therapy was 7.0 (6.0, 12.0) versus 16.5 (9.8, 24.5) days, and the median (interquartile range) HCV-RNA level 3 days after transplant was 6.5 (3.9, 7.1) versus 3.6 (2.9, 4.0) log10  IU/mL in LT versus KT recipients, respectively. By week 4 of treatment, 10 of 13 (77%) LT, but only 2 of 10 (20%) KT, had undetectable HCV RNA (P = 0.01). At the end of treatment, all LT recipients were HCV RNA-undetectable, whereas 3 (30%) of the kidney recipients still had detectable, but not quantifiable, viremia. All achieved sustained virologic response at 12 weeks following transplant (lower 95% confidence interval bound: 85%). Serious adverse events considered possibly related to treatment were antibody-mediated rejection, biliary sclerosis, cardiomyopathy, and graft-versus-host disease, with the latter associated with multiorgan failure, premature treatment discontinuation, and death. CONCLUSIONS: Despite differing kinetics of early HCV infection in liver versus non-liver recipients, a preemptive antiviral strategy is effective. Vigilance for adverse immunologic events is warranted.

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial.

BACKGROUND AND AIMS: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). APPROACH AND RESULTS: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). CONCLUSIONS: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis.

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open-label study, we assessed the histological efficacy of NGM282 in patients with biopsy-confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; -1.9; 95% confidence interval, -2.6 to -1.2; P < 0.001 in the 1 mg group; -2.2, -3.1 to -1.3; P < 0.001 in the 3 mg group) and fibrosis (-0.5; -0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (-58% and -67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; -8% and -9%), alanine aminotransferase (ALT) (-67% and -60%), aspartate aminotransferase (-57% and -52%), and fibrogenesis biomarkers neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3; -22% and -33%) and enhanced liver fibrosis score (ELF; -3% and -6%) at week 12. Greater reductions in Pro-C3, ELF, and cT1, but not in liver fat content, 7alpha-hydroxy-4-cholesten-3-one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open-label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis.

BACKGROUND: NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Herein, we investigate whether administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282. METHODS: In this phase II, open-label, multicenter study, patients with biopsy-confirmed NASH were treated with subcutaneous NGM282 once daily for 12 weeks. After 2 weeks, rosuvastatin was added in stepwise, biweekly incremental doses to a maximum of 40 mg daily. Both drugs were continued until the end of treatment at week 12. We evaluated plasma lipids, lipoprotein particles and liver fat content. RESULTS: In 66 patients who received NGM282 0.3 mg (n = 23), NGM282 1 mg (n = 21), or NGM282 3 mg (n = 22), circulating cholesterol increased from baseline at week 2. Initiation of rosuvastatin resulted in rapid decline in plasma levels of total cholesterol and low-density lipoprotein cholesterol. At week 12, reductions from baseline in total cholesterol levels of up to 18% (p <0.001), low-density lipoprotein cholesterol of up to 28% (p <0.001), triglycerides of up to 34% (p <0.001) and an increase in high-density lipoprotein cholesterol of up to 16% (p <0.001), with similar changes in lipoprotein particles, were observed in these patients. Robust decreases from baseline in 7alpha-hydroxy-4-cholesten-3-one (p <0.001) and liver fat content (p <0.001) were also observed. Rosuvastatin was safe and well-tolerated when co-administered with NGM282 in patients with NASH. CONCLUSIONS: In this multicenter study, NGM282-associated elevation of cholesterol was effectively managed with rosuvastatin. Co-administration of rosuvastatin with NGM282 may be a reasonable strategy to optimize the cardiovascular risk profile in patients with NASH. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) represents a large and growing public health concern with no approved therapy. NGM282, an engineered analogue of the gut hormone FGF19, reduces liver fat, liver injury and inflammation in patients with NASH. However, NGM282 increases cholesterol levels. Here we show that co-administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282, producing a favorable overall lipid profile.

Impact of Prior Bariatric Surgery on Perioperative Liver Transplant Outcomes.

Bariatric surgery (BS) is effective in treating morbid obesity, but the impact of prior BS on candidacy for liver transplantation (LT) is unclear. We examined 78 patients with cirrhosis with prior BS compared with a concurrent cohort of 156 patients matched by age, Model for End-Stage Liver Disease score, and underlying liver disease. We compared rates of transplant denial after evaluation, delisting on the waiting list, and survival after LT. The median time from BS to LT evaluation was 7 years. Roux-en-Y gastric bypass was the most common BS procedure performed (63% of cohort). Nonalcoholic fatty liver disease was the leading etiology for liver cirrhosis (47%). Delisting/death on the waiting list was higher among patients with BS (33.3% versus 10.1%; P = 0.002), and the transplantation rate was lower (48.9% versus 65.2%; P = 0.03). Intention-to-treat (ITT) survival from listing to 1 year after LT was lower in the BS cohort versus concurrent cohort (1-year survival, 84% versus 90%; P = 0.05). On adjusted analysis, a history of BS was associated with an increased risk of death on the waiting list (hazard ratio [HR], 5.7; 95% confidence interval [CI], 2.2-15.1), but this impact was attenuated (HR, 4.9; 95% CI, 1.8-13.4) by the presence of malnutrition. When limited to matched controls by sex, mortality attributed to BS was no longer significant for females (P = 0.37) but was significant for males (P = 0.046). Sarcopenia, as captured by skeletal muscle index, was calculated in a subset of patients (n = 49). The total skeletal surface area was lower in the BS group (127 [105-141] cm2 versus 153 [131-191] cm2 ; P = 0.005). Rates of sarcopenia were higher among patients delisted after listing (71.4% versus 16.7%; P = 0.04). In conclusion, a history of BS was associated with higher rates of delisting on the waiting list as well as lower survival from the time of listing on ITT analysis. Presence of malnutrition and sarcopenia among patients with BS may contribute to worse outcomes.