Objectives: Nonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8–17 years and (2) assess changes in aminotransferases. Methods: Children with NASH were randomized to open-label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent-to-treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed. Results: Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9- and 1.3-fold increase in median C max and AUC0–24, respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of −37.4% (SD 23.8%) at 12 weeks. Conclusions: Once daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH.

Background & Aims: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPAR alpha/delta agonist, in patients with PBC. Methods: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels >= 1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). Results: At 12 weeks, ALP was reduced by -48.3 +/- 14.8% in the elafibranor 80 mg group (p<0.001 vs. placebo) and by -40.6 +/- 17.4% in the elafibranor 120 mg group (p<0.001) compared to a +3.2 +/- 14.8% increase in the placebo group. The composite endpoint of ALP <= 1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0 +/- 25.5% in the elafibranor 80 mg group (p<0.001) and 40.0 +/- 24.1% in the elafibranor 120 mg group (p<0.01) compared to no change (+0.2 +/- 26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. Conclusion: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. Lay summary: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major public health threat and it is dynamic in its natural history of disease progression. The burden of end-stage liver disease due to this condition is projected to increase by 200% to 300% over the next 2 decades.1 This has led to intense drug development efforts to establish effective therapy for this condition.2 Two major approaches are being taken to treat nonalcoholic steatohepatitis (NASH): (1) targeting the metabolic underpinning of the disease and other upstream drivers of disease activity,2 and (2) targeting downstream elements of disease course, such as fibrosis, to reduce disease progression.

Background and Aim: T2D increases the prevalence of steatosis and steatohepatitis (NASH). The aim was to assess the relationship between T2D and two histological features of liver injury defining the need for therapy: disease activity grade (NAS) and fibrotic scar (F). Methods: 2363 patients with metabolic steatosis were screened for the phase 3 elafibranor trial RESOLVE-IT (NTC02704403) with a liver biopsy centrally scored for NAS and F. 71% had obesity, 47% dyslipidemia, 81% MetS. 35% had T2D, 88% of them managed by ≥1 OAD or insulin. Prevalence of active disease (NAS≥4), significant fibrosis (F≥2) and progressive NASH (NAS≥4 with F≥2, i.e., "at-risk" of hepatic outcomes) and clinical and biochemical NASH phenotype was assessed according to the T2D status. Results: The overall prevalence of "at-risk" NASH was 53%, 65% for T2Ds (n=835), and 45% for non-T2Ds (n=1528). T2D was a significant risk factor (p<0.001) for “at-risk” NASH (OR=2.20, 95% CI [1.85;2.62]), NAS≥4 (OR=1.74, 95% CI [1.40;2.16]) and F≥2 (OR=2.50, 95% CI [2.08;3.01]). The association between T2D and “at risk” NASH was independent of age, gender or BMI. T2D patients had higher mean NAS scores (4.96 vs. non-T2Ds: 4.47; p<0.001) and higher mean fibrosis stage (2.17 vs. non-T2D: 1.67; p<0.001). Liver injury markers ALT, AST, GGT or CK18 were higher (p<0.001) in “at-risk” NASH patients but were similar in T2Ds vs. non-T2Ds. Fibrosis serum markers such as TIMP-1, HA, A2M, or P3NP were elevated in “at-risk” NASH patients (p<0.001) and were higher in T2Ds vs. non-T2Ds (p<0.001). In both non-T2D and T2D, HbA1c and glucose homeostasis markers remained higher in “at-risk” NASH (p<0.001). Conclusion: In patients with metabolic steatosis, T2D is associated with necroinflammation and fibrosis and independently increases the risk of developing “at-risk” NASH, highlighting the need for active surveillance of liver injury in T2D patients to identify those in need for clinical intervention. Disclosure B. Staels: None. V. Ratziu: Other Relationship; Self; Gilead Sciences, Inc. A.J. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck & Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate. S. Francque: Consultant; Self; GENFIT. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. A. Roudot: Employee; Self; GENFIT. J. Brozek: Employee; Self; GENFIT. Y. Hajji: Employee; Self; GENFIT. S. Megnien: Employee; Self; GENFIT. D.W. Hum: Employee; Self; GENFIT. P. Birman: Employee; Self; GENFIT. R. Hanf: Employee; Self; GENFIT. B. Cariou: Board Member; Self; Novo Nordisk A/S, Regeneron Pharmaceuticals. Consultant; Self; GENFIT, Sanofi-Aventis. Research Support; Self; Amgen Inc., Pfizer Inc. Speaker’s Bureau; Self; Abbott, Akcea Therapeutics, Merck Sharp & Dohme Corp.

Background and Aim: T2D is an independent risk factor for the development of nonalcoholic steatohepatitis (NASH). Amongst NASH patients, those with elevated disease activity (NAS≥4) and fibrosis (F≥2) upon scoring of a liver biopsy are at higher risk of progressing to negative clinical outcomes. There is a lack of diagnostic tools to identify these “at-risk𠇍 NASH patients that need clinical intervention. Here we compare the ability of NIS4, a novel blood test, to other available tests for detection of “at-risk” NASH in a T2D population. Methods: The blood and liver biopsy samples from 714 patients (446 non-T2D + 268 T2D) with metabolic risk factors for NASH were used. Disease activity (NAS) and fibrosis stage (F) were evaluated by a single expert pathologist. “At-risk” NASH was defined as NASH with NAS≥4 and F≥2. The diagnostic performance of NIS4 to identify patients with “at-risk” NASH in T2D subpopulation was assessed through ROC analysis and compared versus existing tests and statistical comparisons were done by DeLong testing. Results: In the total cohort (T2D prevalence = 38%), AUROC of NIS4 was 0.83 [95% CI: 0.80 - 0.86] for identifying “at-risk” NASH. The prevalence of “at-risk” NASH was higher in T2D (61%) vs. non-T2D (45%). AUROC was comparable in T2D and non-T2D: 0.80 [0.75 - 0.85] vs. 0.83 [0.80 - 0.87]. In T2D, a head to head comparison (AUROC; 95% CI) showed that NIS4 [0.80; 0.75-0.85] significantly outperformed all other tests for the identification of “at-risk” NASH: APRI [0.74; 0.68-0.80], FIB4 [0.70; 0.64-0.77], ELF [0.70; 0.64-0.77], FibroTest [0.68; 0.61-0.74], and NFS [0.60; 0.52-0.67]. Conclusion: Amongst T2D patients with suspected NASH, the prevalence of “at-risk” NASH is high. This highlights the need for active surveillance amongst T2D patients. For that purpose, NIS4 outperforms other tests and is a promising non-invasive tool to identify and potentially track T2D patients who need clinical intervention to manage their disease. Disclosure B. Staels: None. V. Ratziu: Other Relationship; Self; Gilead Sciences, Inc. S. Francque: Consultant; Self; GENFIT. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. P. Bedossa: Consultant; Self; GENFIT. A. Roudot: Employee; Self; GENFIT. Z. Majd: Employee; Self; GENFIT. J. Brozek: Employee; Self; GENFIT. F. Ben-Sudrik: Employee; Self; GENFIT. P. Birman: Employee; Self; GENFIT. D.W. Hum: Employee; Self; GENFIT. S. Hosmane: Employee; Self; GENFIT. P. Chaumat: Employee; Self; GENFIT. R. Hanf: Employee; Self; GENFIT. B. Cariou: Board Member; Self; Novo Nordisk A/S, Regeneron Pharmaceuticals. Consultant; Self; GENFIT, Sanofi-Aventis. Research Support; Self; Amgen Inc., Pfizer Inc. Speaker’s Bureau; Self; Abbott, Akcea Therapeutics, Merck Sharp & Dohme Corp. A. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck & Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate.

OBJECTIVE:To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40-120 mg/week) in acromegaly. DESIGN:This is a 28-week, multicenter, open-label, single-arm sequential study. METHODS:Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40-80 mg once weekly or 40 or 60 mg twice weekly). RESULTS:In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (-0.6 ± 1.6) and soft tissue swelling (-0.6 ± 1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related - thrombocytopenia, urticaria; not treatment related - abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5 × upper limit of normal with normalization after withdrawal). CONCLUSIONS:In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.