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 oneaccompanying 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 endpointsfor 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

Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation

Abstract Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks

Clinical Significance of Immune Deposits and Complement System Activation in FSGS: Findings from the Cure Glomerulonephropathy Network Study

BackgroundThe interplay between complement activation and the immune response in FSGS warrants further investigation. We investigated the association of glomerular C3 and IgM immunostaining with FSGS disease activity, complement system activation, chronicity on kidney biopsy, and initial and follow-up clinical data in the Cure Glomerulonephropathy Network FSGS cohort.MethodsData for patients with FSGS with available pathology assessment from the Cure Glomerulonephropathy Network cohort were reviewed. We tested associations between glomerular immunoglobulins and C3 staining intensity by immunofluorescence with the Columbia classification, the urinary membrane attack complex (soluble C5b9 [sC5b9]) level, proteinuria, and time to a composite outcome, defined by ESKD or a 40% decline in eGFR. Urinary sC5b9 levels, expressed as ratios to creatinine (sC5b9-to-creatinine ratio) and to protein (urine sC5b9-to-creatinine ratio-to-protein ratio [C5b9uPR]), were also examined.ResultsThe study cohort comprised 175 patients with FSGS, including 63 (36%) incident subjects enrolled within 6 months of pathology review. Glomerular IgM, C3, and IgG deposits were found in 88 (50%), 48 (27.4%), and 27 (15.4%) patients, respectively. C3 deposition was correlated with global sclerosis (r=0.27, P < 0.001), tubular microcystic changes (r=0.19, P < 0.01), interstitial fibrosis (IF) tubular atrophy (r=0.17, P = 0.03), interstitial inflammation (r=0.17, P = 0.03), and tip lesion (r=-0.16, P = 0.04). In incident patients, C5b9uPR correlated with total segmental sclerosis (r=0.35, P < 0.01), IF (r=0.33, P = 0.01), IF tubular atrophy (r=0.35, P < 0.01), and interstitial inflammation (r=0.29, P = 0.03). Only C5b9uPR (hazard ratio, 1.64 [95% confidence interval, 1.03 to 2.60; P = 0.03]) and age at enrollment (hazard ratio, 1.01 [95% confidence interval, 1.00 to 1.03; P = 0.02]) were significantly associated with the composite outcome in the adjusted Cox survival models.ConclusionsC5b9uPR is emerging as a significant biomarker for FSGS progression, reflecting the complex interplay between complement activation, inflammation, and kidney injury. The evidence suggests that elevated C5b9uPR levels are associated with poor kidney outcomes and may serve as a valuable tool in the noninvasive assessment of kidney fibrosis and disease progression

Family History in the Context of CKD

Background A family history of health conditions may reflect shared genetic and/or environmental risk. It is not well known to what extent family history affects outcomes among patients with CKD. In this study, we investigated the associations of family history of CKD, diabetes, and other conditions with common comorbidities and kidney disease progression among patients with CKD.MethodsWe performed an observational study of two prospective CKD cohorts, 2573 adults and children from the Cure Glomerulopathy Network and 3939 Chronic Renal Insufficiency Cohort adult participants. Self-reported first-degree family history of CKD, diabetes, and other common diseases was tested for associations with the risk of comorbidities and CKD progression using multivariable models.ResultsFamily history of common comorbid conditions was associated with higher risk of these conditions in the context of CKD, including approximately by over three-fold for diabetes (adjusted odds ratio [OR], 3.37; 95% confidence interval [CI], 2.73 to 4.15), 48% for cancer (adjusted OR, 1.48; 95% CI, 1.05 to 2.09), and 69% for cardiovascular disease (adjusted OR, 1.69; 95% CI, 1.36 to 2.10 in combined cohorts). While polygenic risk score (PRS) for CKD was associated with kidney disease progression (adjusted hazards ratio, 1.11; 95% CI, 1.06 to 1.16 in combined cohorts), family history of kidney disease was not an independent risk factor of disease progression in the context of existing CKD. By contrast, family history of diabetes was significantly associated with a higher risk of CKD progression independently of diabetes occurrence or PRS for diabetes (adjusted hazards ratio, 1.19; 95% CI, 1.05 to 1.35 in combined cohorts).ConclusionsBroad collection of family history in the context of CKD improved clinical risk stratification. Family history of diabetes was consistently associated with a higher risk of CKD progression independently of diabetes status or PRS for diabetes in both cohorts