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

Reassuring Data on the Cardiovascular Risk in Adults With X-linked Hypophosphatemia Receiving Conventional Therapy

International audienceCONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in increased plasma levels of fibroblast growth factor 23 (FGF23). Several studies have demonstrated a direct association between FGF23 and cardiovascular mortality in cohorts of patients with chronic renal failure. However, in patients with XLH, studies on the cardiovascular impact of the disease are rare, with contradictory results. OBJECTIVE: The aim was to assess whether the disease led to an increased cardiovascular risk. METHODS: We conducted a single-center retrospective observational study on a local cohort of adult patients with XLH. The primary endpoint was a composite endpoint of the frequency of left ventricular hypertrophy (LVH) or presence of high blood pressure. Our secondary objectives were to assess echocardiographic, pulse wave velocity, and central blood pressure data as other markers of CV health. Independently of this cohort, tissue sodium content with magnetic resonance imaging was studied in 2 patients with XLH before and after burosumab. RESULTS: Twenty-two patients were included. Median serum phosphate was 0.57 (0.47-0.72) mmol/L and FGF23 94 pg/L (58-2226). Median blood pressure was 124 (115-130)/68 (65-80) mm Hg, with only 9% of patients being hypertensive. A majority of patients (69%) had no LVH, only 1 had a left ventricular mass \textgreater100 g/m² and 25% of patients had left ventricular remodeling. Pulse wave velocity was normal in all patients. No differences in skin and muscle sodium content were observed before and after burosumab in the 2 patients who underwent sodium magnetic resonance imaging. CONCLUSION: We found no elevated risk of developing hypertension or LVH in patients with XLH