Search

Background and aimsENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and resultsPatients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.ConclusionsPatients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Patient-reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo-controlled study of selonsertib, firsocostat, or cilofexor, alone or in two-drug combinations (NCT03449446). PROs included Short Form 36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-NASH, EuroQol Five Dimension (EQ-5D), Work Productivity and Impairment (WPAI), and 5-D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF-36 and Fatigue and Worry of CLDQ-NASH were significantly lower in patients with cirrhosis (total CLDQ-NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α-hydroxy-4-cholesten-3-one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288-439) and 0.7 mg/dL (0.5-1.0), respectively. Dose-dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction -21%; P = 0.029 versus placebo), gamma-glutamyl transferase (-30%; P < 0.001), alanine aminotransferase (ALT) (-49%; P = 0.009), and aspartate aminotransferase (-42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid-treated and untreated patients. At week 12, cilofexor-treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, tissue inhibitor of metalloproteinase 1, C-reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo-treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12-week, randomized, placebo-controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.

BACKGROUND & AIMS:We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS:We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS:The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS:In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Summary: Background: The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min. Aims: Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests. Methods: This study combined the data from two prospectively conducted US studies: HALT‐C and SHUNT‐V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD). Results: DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500). Conclusions: DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs. [ABSTRACT FROM AUTHOR]

Background & aimsThe combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA

Summary: Background: Seladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects. Aims: To evaluate the long‐term safety and efficacy of seladelpar in patients with PBC. Methods: In an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. Results: There were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16. [ABSTRACT FROM AUTHOR]

UnlabelledHepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized, controlled trial to test the efficacy and safety of pretransplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN-α2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or Model for End-Stage Liver Disease upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n = 44/2/1) were randomized 2:1 to treatment (n = 31) or untreated control (n = 16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. Peg-IFN-α2b, starting at 0.75 μg/kg/week, and RBV, starting at 600 mg/day, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pretransplant sustained virologic response and post-transplant virologic response (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (P = 0.29); per-protocol values were 13 (22%) and 0 (0%) (P = 0.03). Among treated G1/4/6 patients, 23 of 30 received transplant, of whom 22% had pTVR; among treated G2/3 patients 21 of 29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for 16 weeks, respectively (P = 0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% versus 55%; P = 0.30), but the number of SAEs per patient was higher in the treated group (2.7 versus 1.3; P = 0.003).ConclusionPretransplant treatment with Peg-IFN-α2b/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications.

Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C. We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred twenty seven participants in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, and perfused hepatic mass (PHM) and liver and spleen volumes (SPECT) were measured. Baseline QLFTs were significantly worse (p=0.0017 to

The gradual accumulation of hepatic fibrosis in chronic liver disease results in clinical complications. The rate of hepatic fibrosis score progression (RFSP) in predicting clinical outcomes was assessed by extending the 4-year Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial to include preenrollment liver biopsies.The RFSP was calculated from the linear regression slope of Ishak fibrosis score vs time in 457 patients with liver biopsies (≥10-mm length) prior to the HALT-C Trial (575 biopsies) plus 1101 on-study biopsies (total 1676 biopsies). Individual slopes were calculated if duration from first to last biopsy was > 4 years.The RFSP as average fibrosis score vs average time in intervals (0-3 and >3 years prestudy, screening, month 24 and 48 on-study) in 455 patients in cohorts of baseline Ishak score ranged from 0.005 with Ishak score 2 to 0.124 with Ishak 6. The RFSP in individual patients (-0.35 to +0.97 Ishak units/year) had a mean of 0.12 ± 0.23 in 344 patients with prestudy and on-study biopsies (group A) and only 0.17 ± 0.22 in 169 with prestudy and screening biopsies (group B). Group A patients with RFSP slope ≥ 0.2 (95 patients, 27.6%) had higher 7-year cumulative rates of non-hepatocellular carcinoma outcomes (46% vs 8%, respectively) and with a hepatocellular carcinoma (10% vs 3%, respectively) than RFSP slope < 02 (249 patients, 72.4%) (P < .0001). RFSP and screening Ishak score correlated independently (P 0.2), which occurred in 26.7% of HALT-C Trial patients, correlated strongly with clinical outcomes.

BackgroundGenetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.MethodsHALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).ResultsAmong 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.ConclusionA clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.